Osteoporosis

Osteoporosis is a chronic, progressive disease of multifactorial etiology (see Etiology) and is the most common metabolic bone disease in the United States. It has been most frequently recognized in postmenopausal women, persons with small bone structure, the elderly, and in whites and Asians, although it does occur in both sexes, all races, and all age groups. Screening of at-risk populations is essential and can identify persons with osteoporosis before fractures occur (see Workup).

Osteoporosis is characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility.[13] The disease often does not become clinically apparent until a fracture occurs.

Osteoporosis represents an increasingly serious health and economic problem in the United States and around the world.[14] Many individuals, male and female, experience pain, disability, and diminished quality of life as a result of having this condition. Over recent decades, osteoporosis has gone from being viewed as an inevitable consequence of aging to being recognized as a serious, eminently preventable and treatable disease.

Despite the adverse effects of osteoporosis, it is a condition that is often overlooked and undertreated, in large part because it is so often clinically silent before manifesting in the form of fracture. Fractures in patients with osteoporosis can occur after minimal or no trauma.[15] For example, a Gallup survey performed by the National Osteoporosis Foundation in 2000 revealed that 86% of women with osteoporosis had never discussed its prevention with their physicians.[16] Failure to identify at-risk patients, to educate them, and to implement preventive measures may lead to tragic consequences.

Medical care includes lifestyle modifications including exercise, smoking cessation, and avoiding excess alcohol intake along with taking calcium, vitamin D, and antiresorptive agents such as bisphosphonates, the selective estrogen receptor modulator (SERM) raloxifene,, and denosumab. Anabolic agents, include: teriparatide, abaloparatide, and romosozumab (see Medication), are available as well.[17]  Prevention and recognition of the secondary causes of osteoporosis are first-line measures to lessen the impact of this condition.

WHO definition of osteoporosis

Bone mineral density (BMD) scores are related to peak bone mass and, subsequently, bone loss. Whereas the T-score is the patient’s bone density compared with the BMD of control subjects who are at their peak BMD, the Z-score reflects a bone density compared with that of patients matched for age and sex.[7, 8, 9, 10]

The World Health Organization’s (WHO) definitions of osteoporosis, which are based on BMD measurements in white women, are summarized in Table 1, below.[9, 10] For each standard deviation (SD) reduction in BMD, the relative fracture risk is increased 1.5-3 times. The WHO definition applies to postmenopausal women and men aged 50 years or older. Although these definitions are necessary to establish the prevalence of osteoporosis, they should not be used as the sole determinant of treatment decisions. This diagnostic classification should not be applied to premenopausal women, men younger than 50 years, or children.

Table 1. WHO Definition of Osteoporosis Based on BMD Measurements by DXA (Open Table in a new window)

The WHO recommends incorporating clinical risk factors into decision making about osteoporosis, rather than relying solely on the use of bone mineral measurements. BMD has high specificity but low sensitivity, meaning that the risk of a fracture is high when the BMD indicates that osteoporosis is present, but is by no means negligible when BMD is normal.[18]

Z-scores should be used in premenopausal women, men younger than 50 years, and children. Z-scores adjusted for ethnicity or race should be used, with Z-scores of –2.0 or lower defined as "below the expected range for age" and with Z-scores above –2.0 being defined as "within the expected range for age." Again, the diagnosis of osteoporosis in these groups should not be based on densitometric criteria alone.

For more information, see the following:

• Pediatric Osteoporosis
• Osteoporosis in Solid Organ Transplantation
• Bone Markers in Osteoporosis
• Nonoperative Treatment of Osteoporotic Compression Fractures

It is increasingly being recognized that multiple pathogenetic mechanisms interact in the development of the osteoporotic state. Understanding the pathogenesis of osteoporosis starts with knowing how bone formation and remodeling occur.

Normal bone formation and remodeling

Bone undergoes both radial and longitudinal growth and is continually remodeled throughout our lives in response to microtrauma.[19] Bone remodeling renews bone strength and mineral, preventing the accumulation of damaged bone.[19] Bone remodeling occurs at discrete sites within the skeleton and proceeds in an orderly fashion, and bone resorption is always followed by bone formation, a phenomenon referred to as coupling.

Dense cortical bone and spongy trabecular or cancellous bone differ in their architecture but are similar in molecular composition. Both types of bone have an extracellular matrix with mineralized and nonmineralized components. The composition and architecture of the extracellular matrix are what imparts mechanical properties to bone. Bone strength is determined by collagenous proteins (tensile strength) and mineralized osteoid (compressive strength).[20] The greater the concentration of calcium, the greater the compressive strength. In adults, approximately 25% of trabecular bone is resorbed and replaced each year, compared with only 3% of cortical bone. Up to 10% of the skeleton is being remodelled at any one time. 

Osteoclasts, derived from hematopoietic precursors, are responsible for bone resorption, whereas osteoblasts, from mesenchymal cells, are responsible for bone formation (see the images below). The 2 types of cells are dependent on each other for production and linked in the process of bone remodeling.

Osteoblasts not only secrete and mineralize osteoid but also appear to control the bone resorption carried out by osteoclasts. Osteocytes, which are terminally differentiated osteoblasts embedded in mineralized bone, direct the timing and location of bone remodeling. In osteoporosis, the coupling mechanism between osteoclasts and osteoblasts is thought to be unable to keep up with the constant microtrauma to trabecular bone. Osteoclasts require weeks to resorb bone, whereas osteoblasts need months to produce new bone and on average bone formation takes 4 to 6 months to be completed. Therefore, any process that increases the rate of bone remodeling results in net bone loss over time.[13]

Bone remodeling has 4 sequential phases: activation precedes resorption, which precedes reversal, which precedes the formation of a new osteon and the process is the same in both cortical spongy trabecular or cancellous bone.[19]  'Activation' is defined as the conversion of bone surface from quiescence to active, which is followed by the differentiation of osteoclast precursors into mature osteoclasts in the ‘resorption’ phase. In the ‘reversal’ phase, osteoclasts complete the resorption process and produce signals that directly or indirectly initiate bone formation, and in the final ‘formation’ phase, mesenchymal cells differentiate into functional osteoblasts to make the bone matrix.

This image depicts bone remodeling with osteoclasts resorbing one side of a bony trabecula and osteoblasts depositing new bone on the other side.

Osteoclast, with bone below it. This image shows typical distinguishing characteristics of an osteoclast: a large cell with multiple nuclei and a "foamy" cytosol.

In this image, several osteoblasts display a prominent Golgi apparatus and are actively synthesizing osteoid. Two osteocytes can also be seen.

Furthermore, in periods of rapid remodeling (eg, after menopause), bone is at an increased risk for fracture because the newly produced bone is less densely mineralized, the resorption sites are temporarily unfilled, and the isomerization and maturation of collagen are impaired.[21]

Activation frequency reflecting the bone remodelling rate increased to double at menopause, triple by 13 years later, and remained at high levels in osteoporotic patients, which contributes to increases in age-related skeletal fragility in women. Bone remodeling increases substantially in the years after menopause and remains increased in older osteoporosis patients.

The receptor activator of nuclear factor-kappa B ligand (RANKL)/receptor activator of nuclear factor-kappa B (RANK)/osteoprotegerin (OPG) system is the final common pathway for bone resorption. Osteoblasts and activated T cells in the bone marrow produce the RANKL cytokine. RANKL binds to RANK expressed by osteoclasts and osteoclast precursors to promote osteoclast differentiation. OPG is a soluble decoy receptor that inhibits RANK-RANKL by binding and sequestering RANKL.[22]

Bone mass peaks around the third decade of life and slowly decrease afterward. A failure to attain optimal bone strength by this point is one factor that contributes to osteoporosis, which explains why some young postmenopausal women have a low bone mineral density (BMD) and why some others have osteoporosis. Therefore, nutrition and physical activity are important during growth and development. Nevertheless, hereditary factors play the principal role in determining an individual's peak bone strength. In fact, genetics account for up to 80% of the variance in peak bone mass between individuals.[13, 23]

Alterations in bone formation and resorption

Osteoporosis is multifactorial with an interplay of genetic, intrinsic, exogenous, and lifestyle factors. [24] The hallmark of osteoporosis is a reduction in skeletal mass caused by an imbalance between bone resorption and bone formation. Under physiologic conditions, bone formation and resorption are in a fair balance. A change in either—that is, increased bone resorption or decreased bone formation—may result in osteoporosis.

Osteoporosis can be caused both by a failure to build bone and reach peak bone mass as a young adult and by bone loss later in life. Accelerated bone loss can be affected by hormonal status, as occurs in perimenopausal women; can impact elderly men and women, and can be secondary to various disease states and medications.

Aging and loss of gonadal function are the two most important factors contributing to the development of osteoporosis. Studies have shown that bone loss in women accelerates rapidly in the first years after menopause. The lack of gonadal hormones is thought to up-regulate osteoclast progenitor cells. Estrogen deficiency leads to increased expression of RANKL by osteoblasts and decreased release of OPG; increased RANKL results in recruitment of higher numbers of preosteoclasts as well as increased activity, vigor, and lifespan of mature osteoclasts.

Estrogen deficiency

Estrogen deficiency not only accelerates bone loss in postmenopausal women but also plays a role in bone loss in men. Estrogen deficiency can lead to excessive bone resorption accompanied by inadequate bone formation. Estrogen deficiency increases the number of osteoclasts and decreases the number of osteoblasts resulting in overall bone resorption. Of note, fracture risk is inversely proportional to the estrogen level in postmenopausal women. [25] Osteoblasts, osteocytes, and osteoclasts all express estrogen receptors. In addition, estrogen affects bones indirectly through cytokines and local growth factors. The estrogen-replete state may enhance osteoclast apoptosis via increased production of transforming growth factor (TGF)–beta.

Estrogen deficiency increases while estrogen treatment decreases the rate of bone remodeling and the amount of bone loss during the remodeling cycle. In the absence of estrogen, T cells promote osteoclast recruitment, differentiation, and prolonged survival via interleukin-1 ( IL-1), IL-6, and tumor necrosis factor (TNF)–alpha. A murine study, in which either the mice's ovaries were removed or sham operations were performed, found that IL-6 and granulocyte-macrophage CFU levels were much higher in the ovariectomized mice.[26] This finding provided evidence that estrogen inhibits IL-6 secretion and that IL-6 contributes to the recruitment of osteoclasts from the monocyte cell line, thus contributing to osteoporosis.

IL-1 has also been shown to be involved in the production of osteoclasts. The production of IL-1 is increased in bone marrow mononuclear cells from ovariectomized rats. Administering IL-1 receptor antagonist to these animals prevents the late stages of bone loss induced by the loss of ovarian function, but it does not prevent the early stages of bone loss. The increase in the IL-1 in the bone marrow does not appear to be a triggered event but, rather, a result of removal of the inhibitory effect of sex steroids on IL-6 and other genes directly regulated by sex steroids.

T cells also inhibit osteoblast differentiation and activity and cause premature apoptosis of osteoblasts through cytokines such as IL-7. Finally, estrogen deficiency sensitizes bone to the effects of parathyroid hormone (PTH).

Osteoimmunology

The term osteoimmunology is defined as the interaction between the skeletal system and the immune system. Osteoclastogenic proinflammatory cytokine in particularly TNF, IL-1, 1L-6, or IL-7 is increased in the first ten years in postmenopausal osteoporotic patients. Of note, Crohn's and rheumatoid arthritis are inflammatory conditions that promote osteoporosis.[27]

T cells are considered to play a role and were found to produce more TNF in postmenopausal women with osteoporotic fracture.[27] Recently, a mechanism was promoted whereby the loss of estrogen results in rapid bone loss by activating low-grade inflammation resulting in osteoporosis in the acute phase of bone catabolic activity in ovariectomized mice.[27] It was found that ovariectomy in mice results in increased dendritic cells which express IL-7 and IL-15  inducing antigen-independent production of IL-17A and TNFα in a subset of memory T cells. The study found that ovariectomized mice with T- cell ablation of IL15RA result in no 1L-17A and TNFα expression and no increase in bone resorption or bone loss.[28]

B lymphocytes play a role in osteoporosis by producing RANKL and OPG which regulates the RANK/ RANKL/OPG axis. Production of RANKL by B-lymphocyte is increased in postmenopausal women. The ablation of RANKL in B cells in mice resulted in partial protection from trabecular bone loss post ovariectomy.[27]

Aging

Postmenopausal bone loss is associated with excessive osteoclast activity. Senile osteoporosis may also be associated with excessive osteoclast activity but there may also be a progressive decline in the supply of osteoblasts in proportion to the demand. This demand is ultimately determined by the frequency with which new multicellular units are created and new cycles of remodeling are initiated.

After the third decade of life, bone resorption exceeds bone formation and leads to osteopenia and, in severe situations, osteoporosis. Women lose 30-40% of their cortical bone and 50% of their trabecular bone over their lifetime, as opposed to men, who lose 15-20% of their cortical bone and 25-30% of trabecular bone. Aging deteriorates bone structure, composition, and function leading to  bone loss being evident before sex steroid deficiency. Aging results in a combination of cortical thinning, increased cortical porosity, thinning of the trabeculae, and loss of trabecular connectivity. [29]

Calcium deficiency

Calcium, vitamin D, and PTH help maintain bone homeostasis. Insufficient dietary calcium or impaired intestinal absorption of calcium due to aging or disease can lead to secondary hyperparathyroidism. PTH is secreted in response to low serum calcium levels. It increases calcium resorption from bone, decreases renal calcium excretion, and increases renal production of 1,25-dihydroxyvitamin D (1,25[OH]2 D)—an active hormonal form of vitamin D that optimizes calcium and phosphorus absorption, inhibits PTH synthesis, and plays a minor role in bone resorption.

Vitamin D deficiency

Vitamin D deficiency is prevalent in the older population and can result in secondary hyperparathyroidism via decreased intestinal calcium absorption.

Osteoporotic fractures

Osteoporotic fractures represent the clinical significance of these derangements in the bone. They can result both from low-energy trauma, such as falls from a sitting or standing position, and from high-energy trauma, such as a pedestrian struck in a motor vehicle accident. Fragility fractures, which occur secondary to low-energy trauma, are characteristic of osteoporosis. The most common osteoporotic fracture includes femoral neck, pathologic fractures of the vertebrae, lumbar and thoracic vertebral fractures, and distal radius fractures. The least common osteoporotic fracture includes open fractures of the proximal humerus and closed fractures of the skull and facial bones.[30]

Nearly all osteoporotic hip fractures are related to falls.[31] The frequency and direction of falls can influence the likelihood and severity of fractures. The risk of falling may be amplified by neuromuscular impairment due to vitamin D deficiency with secondary hyperparathyroidism or to corticosteroid therapy.

Vertebral bodies are composed primarily of cancellous bone with interconnected horizontal and vertical trabeculae. Osteoporosis not only reduces bone mass in vertebrae but also decreases interconnectivity in their internal scaffolding.[20] Therefore, minor loads can lead to vertebral compression fractures.

An understanding of the biomechanics of bone provides greater appreciation as to why bone may be susceptible to an increased risk of fracture. In bones that sustain vertical loads, such as tibial and femoral metaphyses and vertebral bodies, resistance to lateral bowing and fractures is provided by a horizontal trabecular cross-bracing system that helps support the vertical elements. Disruption of such trabecular connections is known to occur preferentially in patients with osteoporosis, particularly in postmenopausal women, making females more at risk than males for vertebral compression fractures (see the images below).

Osteoporosis is defined as a loss of bone mass below the threshold of fracture. This slide (methylmethacrylate embedded and stained with Masson's trichrome) demonstrates the loss of connected trabecular bone.

The bone loss of osteoporosis can be severe enough to create separate bone "buttons" with no connection to the surrounding bone. This easily leads to insufficiency fractures.

Rosen and Tenenhouse studied the unsupported trabeculae and their susceptibility to fracture within each vertebral body and found an extraordinarily high prevalence of trabecular fracture callus sites within vertebral bodies examined at autopsy—typically, 200-450 healing or healed fractures per vertebral body.[32] These horizontal trabecular fractures are asymptomatic, and their accumulation reflects the impact of lost trabecular bone and greatly weakens the cancellous structure of the vertebral body.

The reason for preferential osteoclastic severance of horizontal trabeculae is unknown. Some authors have attributed this phenomenon to overaggressive osteoclastic resorption.

Osteoporosis versus osteomalacia

Osteoporosis may be confused with osteomalacia. The normal human skeleton is composed of a mineral component, calcium hydroxyapatite (60%), and organic material, mainly collagen (40%). In osteoporosis, the bones are porous and brittle, whereas, in osteomalacia, the bones are soft. This difference in bone consistency is related to the mineral-to-organic material ratio. In osteoporosis, the mineral-to-collagen ratio is within the reference range, whereas in osteomalacia, the proportion of mineral composition is reduced relative to organic material content.

The Wnt signaling pathway and bone

The Wnt family is a highly conserved group of proteins that were initially studied in relationship with cancer initiation and progression due to their involvement in intercellular communication.[33] Subsequently, the Wnt signaling cascade was recognized as a critical regulator of bone metabolism.

Wnt signaling plays a key role in the fate of mesenchymal stem cells (MSCs), which are the progenitor cells of mature bone-forming osteoblasts.[34] MSCs have the capability to differentiate into adipocytes, chondrocytes, neurons, and muscle cells, as well as into osteoblasts.[35] Certain Wnt signaling pathways promote the differentiation of MSCs along the osteoblast lineage. The emerging details about the specific molecules involved in the Wnt pathway have improved the understanding of bone metabolism and led to the development of new therapeutic targets for metabolic bone diseases.

Wnt signal activation may progress along one of three pathways, with the “canonical” pathway involving β-catenin being most relevant to bone metabolism. The canonical Wnt signaling pathway is initiated by the binding of a Wnt protein to an extracellular co-receptor complex consisting of “Frizzled” (Fr) and low-density lipoprotein receptor-related protein–5 or –6 (LRP5, LRP6).[36] This activation recruits another protein, “Disheveled” (Dvl) to the intracellular segment of the Fz/Dvl co-receptor.[37] This is where β-catenin comes into play.

β-Catenin is an important intracellular signaling molecule and normally exists in a phosphorylated state targeted for ubiquination and subsequent degradation within intracellular lysosomes. Activation of the Wnt pathway leads to dephosphorylation and stabilization of intracellular β-catenin and rising cytosolic concentrations of β-catenin. As the concentration of β-catenin reaches a critical level, β-catenin travels to the nucleus, where it activates the transcription of Wnt target genes. Ultimately, canonical Wnt signaling inhibits the expression of transcription factors important in the differentiation of MSCs such as peroxisome proliferator-activated receptor gamma (PPAR-γ) and promotes survival of osteoblast lineage cells.[38]

Several human bone abnormalities have been linked to the Wnt pathway. For example, a single amino acid substitution in the LRP5 receptor gene has been associated with high bone mass phenotypes in humans; specifically, the mutant LRP5 receptor had an impaired interaction with the Wnt signal inhibitor Dickkopf-1 (Dkk-1).[39] Similarly, other missense mutations of LRP5 have been implicated in other high bone mass diseases such as Van Buchem disease and osteopetrosis.[40] Conversely, loss-of-function mutations of LRP5 have resulted in a rare but severe congenital osteoporosis in humans.[41]

There are also several antagonists to the Wnt pathway. Two of the most well-known are Dkk-1 and sclerostin. Dkk-1 is secreted by MSCs[42] and binds to LRP-5 and LRP-6,[43] thereby competitively inhibiting Wnt signaling. Interestingly, serum levels of Dkk-1 positively correlate with the extent of lytic bone lesions in patients with multiple myeloma.[44]  In animal models, anti-Dkk1 monoclonal antibody accelerates bone formation and increases bone mineral density, and anti-Dkk antibody is under development as a bone-anabolic agent.[45]

Similarly, sclerostin, a product of osteocytes,[46] has also been found to antagonize the Wnt signaling pathway by binding to LRP5 and LRP6.[47] Romosozumab, a monoclonal antibody that binds with and inhibits sclerostin, and thus both increases bone formation and decreases bone resorption, has been approved for the treatment of osteoporosis in postmenopausal women who are at high risk for fracture.[48]

Additional factors and conditions

Endocrinologic conditions or medications that lead to bone loss (eg, glucocorticoids) can cause osteoporosis. Corticosteroids inhibit osteoblast function and enhance osteoblast apoptosis.[49] Polymorphisms of IL-1, IL-6, and TNF-alpha, as well as their receptors, have been found to influence bone mass.

Other factors implicated in the pathogenesis of osteoporosis include the following[13] :

• Polymorphisms in the vitamin D receptor
• Alterations in insulin-like growth factor-1, bone morphogenic protein, prostaglandin E ₂, nitrous oxide, and leukotrienes
• Collagen abnormalities
• Leptin-related adrenergic signaling

Epigenetics

Prenatal and postnatal factors contribute to adult bone mass. In one study, the health of the mother in pregnancy, the infant’s birth weight, and the child’s weight at age 1 year were predictive of adult bone mass in the seventh decade for men and women.[50] It is postulated that growth in the first year of life programs growth hormone secretion, and that this programming is maintained into the seventh decade.[51] Higher birth weight and rapid growth in the first year of life predicted increased bone mass in adults aged 65-75 years. Maternal nutritional imbalance and deficiency may have an effect that is transmitted to the next generation.[52]

Etiologically, osteoporosis is categorized as primary or secondary.

Primary osteoporosis

Primary osteoporosis is the most common form of osteoporosis. It is divided into juvenile and idiopathic osteoporosis; idiopathic osteoporosis can be further subdivided into postmenopausal (type I) and age-associated or senile (type II) osteoporosis. Postmenopausal osteoporosis is primarily due to estrogen deficiency. Senile osteoporosis is primarily due to an aging skeleton and calcium deficiency. SeeTable 2, below.

Table 2. Types of Primary Osteoporosis (Open Table in a new window)

Secondary osteoporosis

Secondary osteoporosis occurs when an underlying disease, deficiency, or drug causes osteoporosis (see Table 3, below).[53] Up to one-third of postmenopausal women, as well as many men and premenopausal women, have a coexisting cause of bone loss,[11, 54] of which renal hypercalciuria is one of the most important secondary causes of osteoporosis and treatable with thiazide diuretics.[55]

Table 3. Causes of Secondary Osteoporosis in Adults (Open Table in a new window)

Risk factors

Risk factors for osteoporosis, such as advanced age and reduced bone mineral density (BMD), have been established by virtue of their direct and strong relationship to the incidence of fractures; however, many other factors have been considered risk factors based on their relationship to BMD as a surrogate indicator of osteoporosis.

Risk factors for osteoporosis include the following[62, 63, 64] :

• Advanced age (≥50 years)
• Female sex
• White or Asian ethnicity
• Genetic factors, such as a family history of osteoporosis
• Thin build or small stature (eg, bodyweight less than 127 lb [57.6 kg])
• Amenorrhea
• Late menarche
• Early menopause
• Postmenopausal state
• Physical inactivity or immobilization ^[65]
• Use of certain drugs (eg, anticonvulsants, systemic steroids, thyroid supplements, heparin, chemotherapeutic agents, insulin)
• Alcohol and tobacco use
• Androgen ^[66] or estrogen deficiency
• Calcium or vitamin D deficiency
• Dowager hump

A potentially useful mnemonic for osteoporotic risk factors is OSTEOPOROSIS, as follows:

• L Ow calcium intake
• Seizure meds (anticonvulsants)
• Thin build
• Ethanol intake
• Hyp Ogonadism
• Previous fracture
• Thyr Oid excess
• Race (white, Asian)
• Other relatives with osteoporosis
• Steroids
• Inactivity
• Smoking

Exposure to the antibacterial agent triclosan may increase the risk for osteoporosis in women. Analysis of data on 1848 women from the 2005-2010 US National Health and Nutrition Examination Survey (NHANES) showed that women in the highest tertile of urinary triclosan level had lower BMD in the total femur, intertrochanter, and lumbar spine; compared with women in the lowest tertile, those in the highest tertile were more likely to have increased prevalence of intertrochanter osteoporosis (odds ratio (OR)=2.464, 95% CI = 1.190, 5.105).[67]

In animal studies, triclosan has been found to disrupt hormone activity, and in vitro studies have shown that it can cause interstitial collagen accumulation and an increase in trabecular bone. The US Food & Drug Administration has banned triclosan from consumer hand sanitizers and other antiseptics, but it continues to be used in a variety of consumer products—including clothing, kitchenware, furniture, and toys—to prevent bacterial contamination.[67]

According to the National Osteoporosis Foundation (NOF), in the United States in 2010 more than 10 million adults age 50 years and older had osteoporosis and more than 43 million had low bone mineral density (BMD). In the United States in 2015, as many as 2 million Medicare beneficiaries sustained 2.3 million osteoporotic fractures. Within 12 months of experiencing a new osteoporotic fracture, approximately 15% of patients suffered one or more subsequent fractures and nearly 20% died. Mortality was highest in those with hip fracture, with 30% dying within 12 months.[68] The NOF reported in 2018 that approximately 10.2 million adults in the United States have osteoporosis, with an additional 43.4 million having low bone mass.

Most studies assessing the prevalence and incidence of osteoporosis use the rate of fracture as a marker for the presence of this disorder, although BMD also relates to risk of disease and fracture. The risk of new vertebral fractures increases by a factor of 2-2.4 for each standard deviation (SD) decrease of BMD measurement. Women and men with metabolic disorders associated with secondary osteoporosis have a 2- to 3-fold higher risk of hip and vertebral fractures.

Globally, osteoporosis is by far the most common metabolic bone disease, estimated to affect over 200 million people worldwide.[69] An estimated 75 million people in Europe, the United States, and Japan have osteoporosis.[70]

Age- and sex-related demographics

The risk for osteoporosis increases with age as BMD declines. Senile osteoporosis is most common in persons aged 70 years or older. Secondary osteoporosis, however, can occur in persons of any age. Although bone loss in women begins slowly, it speeds up around the time of menopause, typically at about age 50 years or later. The frequency of postmenopausal osteoporosis is highest in women aged 50-70 years.

The number of osteoporotic fractures increases with age. Wrist fractures typically occur first, when individuals are aged approximately 50-59 years.

Vertebral fractures occur more often in the seventh decade of life. Jensen et al studied Danish women aged 70 years and found a 21% prevalence of vertebral fractures.[71] Melton et al reported that 27% of women in their study had evidence of vertebral fractures by age 65 years.[72]

Ninety percent of hip fractures occur in persons aged 50 years or older, occurring most often in the eighth decade of life.[73]

Women are at a significantly higher risk for osteoporosis. Half of all postmenopausal women will have an osteoporosis-related fracture during their lifetime; 25% of these women will develop a vertebral deformity, and 15% will experience a hip fracture.[74] Risk factors for hip fracture are similar in different ethnic groups.[75]

Men have a higher prevalence of secondary osteoporosis, with an estimated 45-60% of cases being a consequence of hypogonadism, alcoholism, or glucocorticoid excess.[59] Only 35-40% of osteoporosis diagnosed in men is considered primary in nature. Overall, osteoporosis has a female-to-male ratio of 4:1.

Although loss of BMD is typically associated with postmenopausal women, a study to assess the likelihood of low BMD and related risk factors for osteoporosis in men and women aged 35 to 50 years found higher rates of osteopenia in men: 28% of men and 26% of women had osteopenia at the femoral neck region, and 6% and 2%, respectively, had osteoporosis of the lumbar spine. Of the 173 study subjects, 92 (53%) were women and 162 (94%) were white; none had previous known health issues or were taking medications that can affect BMD.[76]

Fifty percent of all women and 21% of all men older than 50 years experience one or more osteoporosis-related fractures in their lifetime.[77] Eighty percent of hip fractures occur in women.[73] Women have a two-fold increase in the number of fractures resulting from nontraumatic causes, as compared with men of the same age.

Racial demographics

Osteoporosis can occur in persons of all races and ethnicities. In general, however, whites (especially of northern European descent) and Asians are at increased risk. In particular, non-Hispanic white women and Asian women are at higher risk for osteoporosis. In the most recent government census, 178 million Chinese were over age 60 years in 2009, a number that the United Nations estimates may reach 437 million—one-third of the population—by 2050.[78]

These numbers suggest that approximately 50% of all hip fractures will occur in Asia in the next century. In fact, although age-standardized incidence rates of fragility fractures, particularly of the hip and forearm, have been noted to be decreasing in many countries over the last decade, that is not the case in Asia.[79]

Table 4, below, summarizes some osteoporosis prevalence statistics among racial/ethnic groups. Note that this disease is under-recognized and undertreated in white and black women. Relative to other racial/ethnic groups, the risk of developing osteoporosis is increasing fastest among Hispanic women.

Table 4. Prevalence of Osteoporosis Among Racial and Ethnic Groups (Open Table in a new window)

Melton et al reported that the prevalence of hip fractures is higher in white populations, regardless of geographic location.[80] Another study indicated that, in the United States and South Africa, the incidence of hip fractures was lower in Black persons than in age-matched white persons. Cauley et al found that the absolute fracture incidence across BMD distribution was 30-40% lower in Black women than in white women. This lower fracture risk was independent of BMD and other risk factors.[81]

The prognosis for osteoporosis is good if bone loss is detected in the early phases and proper intervention is undertaken. Patients can increase bone mineral density (BMD) and decrease fracture risk with exercise, a diet rich in calcium, and the appropriate anti-osteoporotic medication. In addition, patients can decrease their risk of falls by participating in a multifaceted approach that includes rehabilitation and environmental modifications. Worsening of medical status can be prevented by providing appropriate pain management and, if indicated, orthotic devices.

Effect of fractures on prognosis

Many individuals experience morbidity associated with pain, disability, and diminished quality of life caused by osteoporosis-related fractures. According to a 2004 Surgeon General's report, osteoporosis and other bone diseases are responsible for about 1.5 million fractures per year. Osteoporosis-related fractures result in annual direct care expenditures of $12.2 billion to $17.9 billion.[82] In 2005, over 2 million osteoporosis-related fractures occurred in the United States.[83]  A report in 2019 by the National Osteoporosis Foundation noted that an estimated 2 million Americans on Medicare suffered 2.3 million osteoporosis-related bone fractures in 2015.[68]

Osteoporosis is the leading cause of fractures in the elderly. Women aged 50 years have about a 50% lifetime fracture rate as a result of osteoporosis. Osteoporosis is associated with 80% of all fractures in people aged 50 years or older. Approximately 33% of women who live to age 90 years will suffer a hip fracture, which is associated with functional decline, nursing home placement, and death.[84]

Researchers analyzed data from a subgroup of the Study of Osteoporotic Fractures, a prospective cohort study that began recruiting in 1986. The study had 1528 participants, all of whom were women, with a mean (SD) age of 84.1 (3.4) years. During follow-up, 125 (8.0%) women experienced a hip fracture and 287 (18.8%) died before experiencing this event. Five-year mortality probability was 24.9% (95% CI, 21.8-28.1) among women with osteoporosis and 19.4% (95% CI, 16.6-22.3) among women without osteoporosis but at high fracture risk. In both groups, mortality probability similarly increased with more comorbidities and poorer prognosis. In contrast, 5-year hip fracture probability was 13.0% (95% CI, 10.7-15.5) among women with osteoporosis and 4.0% (95% CI, 2.8-5.6) among women without osteoporosis but at high fracture risk. The difference was most pronounced among women with more comorbidities or worse prognosis. For example, among women with 3 or more comorbid conditions, hip fracture probability was 18.1% (95% CI, 12.3-24.9) among women with osteoporosis vs 2.5% (95% CI, 1.3-4.2) among women without osteoporosis but at high fracture risk.[84]

If full recovery is not achieved, osteoporotic fractures may lead to chronic pain, disability, and, in some cases, death. This is particularly true of vertebral and hip fractures.

Vertebral fractures

Vertebral compression fractures are the most common osteoporotic fracture in the United States with an estimated 700,000 per year. [85] Vertebral compression fractures (see the images below) are associated with increased morbidity and mortality rates. In addition, the impact of vertebral fractures increases as they increase in number. As posture worsens and kyphosis progresses, patients experience difficulty with balance, back pain, respiratory compromise, and an increased risk of pneumonia. Overall function declines, and patients may lose their ability to live independently.

Osteoporosis. Lateral radiograph demonstrates multiple osteoporotic vertebral compression fractures. Kyphoplasty has been performed at one level.

Osteoporosis. Lateral radiograph of the patient seen in the previous image following kyphoplasty performed at 3 additional levels.

In one study, Cooper et al found that vertebral fractures increased the 5-year risk of mortality by 15%.[86] In a subsequent study, Kado et al[87] demonstrated that women with one or more fractures had a 1.23-fold increased age-adjusted mortality rate and that women with 5 or more vertebral fractures had a 2.3-fold increased age-adjusted mortality rate.

Furthermore, the mortality rate correlated with number of vertebral fractures: there were 19 deaths per 1000 woman-years in women with no fracture, versus 44 per 1000 woman-years in women with five or more fractures. Vertebral fractures related to risk of subsequent cancer and pulmonary death and severe kyphosis was further correlated with pulmonary deaths.

Symptoms of vertebral fracture may include back pain, height loss, and disabling kyphosis. Compression deformities can lead to restrictive lung disease, abdominal pain, and early satiety.

Hip fractures

More than 250,000 hip fractures are attributed to osteoporosis each year. Like vertebral fractures, they are associated with significantly increased morbidity and mortality rates in men and women. In the year following hip fracture, excess mortality rates can be as high as 20%.[86, 88] Men have higher mortality rates following hip fracture than do women.

Patients with hip fractures incur decreased independence and a diminished quality of life. Of all patients with hip fracture, approximately 20% require long-term nursing care.[4] Among women who sustain a hip fracture, 50% spend time in a nursing home while recovering. Approximately 50% of previously independent individuals become partially dependent, and one third become completely dependent.[89] Only one-third of patients return to their pre-fracture level of function.[90]

Secondary complications of hip fractures include nosocomial infections and pulmonary thromboembolism.

Additional fractures

Patients who have sustained one osteoporotic fracture are at increased risk for developing additional osteoporotic fractures.[70] For example, the presence of at least one vertebral fracture results in a 5-fold increased risk of developing another vertebral fracture. One in 5 postmenopausal women with a new vertebral fracture incurs another vertebral fracture within one year.[91]

Patients with previous hip fracture have a two-fold[92] to 10-fold increased risk of sustaining a second hip fracture. In addition, patients with ankle, knee, olecranon, and lumbar spine fractures have a 1.5-, 3.5-, 4.1-, and 4.8-fold increased risk of subsequent hip fracture, respectively. Site of prior fracture impacts on future risk of osteoporotic fractures independent of BMD such that in postmenopausal women, prior fractures of the spine, humerus, patella, and pelvis are more predictive of future osteoporotic fractures than fractures at other sites.[93]

Fracture risk tools

The fracture risk algorithm (FRAX) was developed to calculate the 10-year probability of a hip fracture and the 10-year probability of any major osteoporotic fracture (defined as clinical spine, hip, forearm, or humerus fracture) in a given patient. These calculations, which are adapted to different geographical locations, account for femoral neck BMD and other clinical risk factors, as follows[94] :

• Age
• Sex
• Personal history of fracture
• Low body mass index
• Use of oral glucocorticoid therapy
• Secondary osteoporosis (eg, coexistence of rheumatoid arthritis)
• Parental history of hip fracture
• Current smoking status
• Alcohol intake (three or more drinks per day)

The National Osteoporosis Foundation (NOF) recommends osteoporosis treatment in patients with low bone mass in whom a US-adapted FRAX 10-year probability of a hip fracture is 3% or more or in whom the risk for a major osteoporosis-related fracture is 20% or more.[4] Note that osteoporosis is, by definition, present in those with a fragility fracture, irrespective of their T-score.

Algorithms such as FRAX are useful in identifying patients with low bone mass (T-scores in the osteopenic range) who are most likely to benefit from treatment. A study by Leslie et al demonstrated the effects of including a patient's 10-year fracture risk along with DXA results in Manitoba, Canada.[95] The authors found an overall reduction in dispensation of osteoporosis medications as more women were reclassified into lower fracture risk categories.

Although type 2 diabetes mellitus (DM) is associated with a higher BMD, a study by Schwartz et al concluded that for a given T score and age or for a given FRAX score, the risk of fracture is higher in patients with type 2 DM than in those without type 2 DM. The study conclusions were based on data from three prospective observational studies, statistics from self-reported incidence of fractures in 9449 women and 7436 men in the United States.[96]

The FRAX tool has a low sensitivity for predicting fracture risk in perimenopausal and early-menopausal women. In a study by Trémollieres et al, FRAX had 50% sensitivity in the 30% of women in the study who were at the highest risk.[97] FRAX also does not include risk of falls; 90% of hip fractures[98] and the majority of Colles fractures are associated with falls.[99]  

The Garvan fracture risk tool is not as widely used as the FRAX but is another validated fracture prediction tool that does account for falls, and maybe a better tool for use in men.[100] However, the Garvan fracture does not include variables like parental history of hip fracture, secondary osteoporosis, rheumatoid arthritis, glucocorticoid use, smoking, or intake of alcohol which are included in the FRAX tool.[101]

Another fracture risk assessment tool is the Qfracture tool history of smoking, alcohol, corticosteroid use, parental history, and secondary causes of osteoporosis but unlike the FRAX tool, it includes history of falls but does not include BMD.[101]

Complications

Vertebral compression fractures often occur with minimal stress, such as coughing, lifting, or bending. The vertebrae of the middle and lower thoracic spine and upper lumbar spine are involved most frequently. In many patients, vertebral fracture can occur slowly and without symptoms. Only one-third of people with radiographic vertebral fractures are diagnosed clinically.[102]

Hip fractures are the most devastating and occur most commonly at the femoral neck and intertrochanteric regions (see the image below). Hip fractures are associated with falls. The likelihood of sustaining a hip fracture during a fall is related to the direction of the fall. Fractures are more likely to occur in falls to the side because less subcutaneous tissue is available to dissipate the impact. Secondary complications of hip fractures include nosocomial infections and pulmonary thromboembolism.

Stable intertrochanteric fracture of the femur.

Fractures can cause further complications, including chronic pain from vertebral compression fractures and increased morbidity and mortality secondary to vertebral compression fractures and hip fractures. Patients with multiple fractures have significant pain, which leads to functional decline and a poor quality of life (QOL).[103] They are also at risk for the complications associated with immobility, including deep vein thrombosis (DVT) and pressure ulcers. Respiratory compromise can occur in patients with multiple vertebral fractures that result in severe kyphosis.

Patients with osteoporosis develop spinal deformities and a dowager's hump, and they may lose 1-2 inches of height by their seventh decade of life. These patients can lose their self-esteem and are at increased risk for depression.

Patient education is paramount in the treatment of osteoporosis. Many patients are unaware of the serious consequences of osteoporosis, including increased morbidity and mortality, and only become concerned when osteoporosis manifests in the form of fracture; accordingly, it is important to educate them regarding these consequences. Early prevention and treatment are essential in the appropriate management of osteoporosis.

The focus of patient education is on the prevention of osteoporosis. Prevention has 2 components, behavior modification, and pharmacologic interventions. Appropriate preventive measures may include adequate calcium and vitamin D intake, exercise, cessation of smoking, and moderation of alcohol consumption (see Treatment/Dietary Measures and Treatment/Prevention.)

Patients should be educated about the risk factors for osteoporosis, with a special emphasis on family history and the effects of menopause. Patients also need to be educated about the benefits of calcium and vitamin D supplements, as well as strategies to prevent falls in the elderly (see Primary Care–Relevant Interventions to Prevent Falling in Older Adults: A Systematic Evidence Review for the US Preventive Services Task Force [USPSTF]).

All postmenopausal women older than 65 years should be offered bone densitometry; densitometry should also be offered to younger women and men who are at elevated risk. These patients should understand the benefits of bone density monitoring. Society at large also should be educated about the benefits of exercise with regard to osteoporosis.

For patient education information, see Osteoporosis, Osteoporosis and Calcium, Osteoporosis FAQs, and Osteoporosis in Men.

Keep in mind that osteoporosis occurs in many people who have few or no risk factors for this condition. Often, patients who have not sustained a fracture do not report symptoms that would alert the clinician to suspect a diagnosis of osteoporosis; thus, this disease is a "silent thief" that generally does not become clinically apparent until a fracture occurs.

Screening at-risk populations is, therefore, essential; unfortunately, many women do not receive proper screening or treatment for osteoporosis, which, in turn, may result in improper management of this disease and its related complications.[104] For example, the  presence of a disorder known to cause secondary osteoporosis—such as rheumatoid arthritis, celiac disease, or Crohn disease—should increase a clinician’s suspicion that the patient may have osteoporosis and that screening may be indicated.

Multiple risk factors exist for osteoporosis. The National Osteoporosis Foundation (NOF) has categorized these risk factors into two categories: nonmodifiable and modifiable. Nonmodifiable risk factors include the following:

• Personal history of fracture as an adult
• History of fracture in a first-degree relative
• White race
• Advanced age
• Female sex
• Dementia
• Poor health or fragility

Potentially modifiable risk factors include the following:

• Current cigarette smoking
• Low body weight (< 127 lb)
• Estrogen deficiency such as that caused by early menopause (age < 45 years) or bilateral ovariectomy and prolonged premenopausal amenorrhea (>1 year)
• Low lifelong calcium intake
• Alcoholism ^[74]
• Impaired eyesight despite adequate correction
• Recurrent falls
• Inadequate physical activity
• Poor health or frailty

Assessment of fracture risk

A thorough history should be obtained to screen for and identify the presence of known risk factors for osteoporosis and osteoporotic fracture. Specifically, the history should focus on the following[105, 106] :

• Age (> 50 years), sex (female), and race (white or Asian)[105] ; the US Preventive Services Task Force (USPSTF) recommendations include screening for osteoporosis in women aged 65 years or older and in younger women with a fracture risk that is the same or greater than that of a 65-year-old white woman who has no additional risk factors[106]

• Family history of osteoporosis, particularly maternal history of fractures

• Reproductive factors, especially regarding early menopause and estrogen replacement therapy: postmenopausal women are at high risk, as are women who have undergone hysterectomy and oophorectomy

• Hypogonadal states: men with hypogonadism secondary to any genetic or other conditions are at higher risk[105] ; the USPSTF notes that there is insufficient current evidence to assess the risk versus benefit of screening for osteoporosis in men[106]

• Smoking: smokers are at higher risk

• Alcohol consumption

• Low levels of physical activity: immobility increases the risk[65] ; spinal cord injury and stroke cause physical impairment and are common causes of immobility

• Strenuous exercise that results in amenorrhea (such as that which occurs in marathon runners)

• Calcium and vitamin D intake

• History of low-trauma "fragility" fracture in patients aged 40 years or older: a fragility fracture is defined as a fracture due to trauma that would not normally cause fracture (a force equal to or less than that resulting from a fall from standing height)

• Signs of vertebral fracture (see below)

• Coexisting medical conditions associated with bone loss: examples are hyperparathyroidism, hypogonadism, leukemia, rheumatoid arthritis, celiac disease, and Cushing syndrome[107]

• Medications associated with bone loss: examples are glucocorticoids, cyclosporine, anticonvulsants, heparin, lithium, and tacrolimus[107]

• Risk factors for falls in older patients: these include poor balance, orthostatic hypotension, weakness of the lower extremity muscles and deconditioning, use of medications with sedative effects, poor vision or hearing, and cognitive impairment

FRAX tool

The USPSTF did not find any studies that assessed whether patient outcomes are affected by the use of risk prediction instruments, either alone or in combination with bone measurement tests. Nevertheless, there are many validated instruments for predicting the risk for low bone mineral density (BMD) in postmenopausal women; few of these, however, have been validated for use in men.[106]

The Fracture Risk Assessment (FRAX) tool, accessible to healthcare providers and patients, is a validated instrument used to estimate 10-year risks for fractures, including those for black, Asian, and Hispanic women.[94] A 65-year-old white woman with no other risk factors has a 9.3% 10-year risk for any osteoporotic fracture. Generally, estimated fracture risks in nonwhite women are lower than those for white women of the same age.

Examples of white women aged 50 to 64 years with ≥10-year fracture risks, based on specific risk factors, include the following[106] :

• A 50-year-old current smoker with a body mass index (BMI) less than 21 kg/m ², daily alcohol use, and parental fracture history
• A 55-year-old woman with a parental fracture history
• A 60-year-old woman with a BMI less than 21 kg/m ² and daily alcohol use
• A 60-year-old current smoker with daily alcohol use

Differentiating fracture types by history

Patients with acute insufficiency fractures may report a history of minimal or no trauma resulting in pain. They may report a fall from a standing or sitting position. Patients with compression fractures resulting in thoracic kyphosis may report iliocostal friction with associated abdominal protrusion, decreased tolerance for oral intake, and breathing difficulties. Patients with hip, pelvic, or sacral fractures may report pain that is worsened with weight-bearing.

Patients who have sustained a vertebral compression fracture may note progressive kyphosis with loss of height. They may also present with an episode of acute back pain after bending, lifting, or coughing. It should be noted, however, that two thirds of vertebral fractures are asymptomatic.

With respect to those vertebral fractures that are painful, typical subjective information may include the following:

• The episode of acute pain may follow a fall or minor trauma.
• Pain is localized to a specific, identifiable, vertebral level in the midthoracic to lower thoracic or upper lumbar spine.
• The pain is described variably as sharp, nagging, or dull; movement may exacerbate pain; in some cases, pain radiates to the abdomen.
• Pain is often accompanied by paravertebral muscle spasms exacerbated by activity and decreased by lying supine.
• Patients often remain motionless in bed because they are afraid of exacerbating the pain.
• Acute pain usually resolves after 4-6 weeks; in the setting of multiple fractures with severe kyphosis, the pain may become chronic.

Patients who have sustained a hip fracture may experience the following:

• Pain in the groin, posterior buttock, anterior thigh, medial thigh, and/or medial knee during weight-bearing or attempted weight-bearing of the involved extremity
• Diminished hip range of motion (ROM), particularly internal rotation and flexion
• External rotation of the involved hip while in the resting position

Patients with osteoporosis may report lactose intolerance or celiac sprue. Celiac sprue has been shown to be associated with osteoporosis in approximately 5% of cases.

Patients with suspected osteoporosis should undergo a comprehensive physical examination. The physical examination should begin with an inspection of the patient. Height measurement with a stadiometer at each visit may be useful. Examination of active and passive range of motion (ROM) assists in determining whether spine, hip, wrist, or other osseous pathology may be present. A thorough neurologic examination is essential to rule out spinal cord and/or peripheral nerve compromise.

The examination may elicit pain, or the patient may be pain free. Thoracic kyphosis may be present secondary to vertebral compression fractures, a dowager hump, and a history of loss of height. Patients may have an associated scoliosis.

Areas of concern include the following:

• A history of loss of height
• Low body weight (body mass index < 19 kg/m ²)
• Signs that might indicate existing osteoporosis (eg, kyphosis or dowager hump; point tenderness over a vertebra or other suspected fracture site)
• Signs suggestive of secondary osteoporosis
• Signs in older patients that may indicate increased fall risk (eg, difficulty with balance or gait, orthostatic hypotension, lower-extremity weakness, poor vision or hearing, cognitive impairment)

A 10-year longitudinal study assessed the Timed Up and Go (TUG) test performance (a validated predictor of falling) and hip area BMD (bone mineral density calculated using bone area as opposed to bone volume). Using data from 1126 women (mean age, 75 years), the study noted that risks of nonvertebral fracture and hip fracture were significantly higher in those who had slow TUG test performance and normal hip BMD or both slow TUG test performance and low hip BMD. These results suggest that the TUG test is an independent risk factor for incident nonvertebral fracture; this inexpensive physical assessment may be beneficial in screening patients at increased risk of fracture.[108]

Signs of fracture

Patients with vertebral compression fractures may demonstrate a thoracic kyphosis with an exaggerated cervical lordosis (dowager hump). This is followed by a loss of lumbar lordosis. After each episode of vertebral compression fracture and progressive kyphosis, the patient's height may decrease by 2-3 cm.

Patients with acute vertebral fractures may have point tenderness over the involved vertebrae. Palpation of the spinous processes often does not aid the examiner in localizing point tenderness, but percussion may be helpful in acute or subacute vertebral compression fractures.

Patients with hip fractures may have severe pain with ambulation. A FABER (flexion in abduction and external rotation) hip joint test may reveal limited ROM with end-range pain. Patients with hip fractures may show decreased weight-bearing on the fractured side or an antalgic gait pattern.

Patients with pubic and sacral fractures may report marked pain with ambulation and tenderness to palpation, percussion, or both. Furthermore, patients with sacral fractures may have pain with physical examination techniques used to assess the sacroiliac joint, such as the FABER, Gaenslen, or squish test.

Fractures in other parts of the body, including the distal radius and humerus, are typically painful and result in limited range of motion of the involved joint.

Signs of collagen defects

Patients with osteoporosis may have physical findings consistent with subtle collagen defects. These include a short fifth digit, dentinogenesis imperfecta, hyperlaxity, hearing loss, pes planus, bunions, and blue sclerae.

Balance difficulties

Patients with osteoporosis are known to have decreased balance, possibly secondary to differences in balance control strategies and sway amplitude. Patients may have difficulty performing tandem gait and performing single limb stance. Poor balance may be noted particularly in patients with severe kyphosis resulting from vertebral compression fractures because their altered center of gravity makes ambulation with a stable base of support difficult for them.[3]

Fractures are the most common and serious complication of osteoporosis. Patients with osteoporosis are at high risk for recurrent fractures of the hips, vertebrae, ribs, and wrists.

Although routinely screening men for osteoporosis is not as widespread a practice as that of screening in women, the US Preventive Services Task Force (USPSTF) indicates that using bone measurement tests in men may not only help to detect this disease but also prevent its associated burden of fractures and fracture-related illness.[109]  Approximately 30% of all hip fractures occur in men and the mortality is higher in men than in women. 

In weighing the risk versus benefit of screening men, clinicians should consider that osteoporosis is a preventable condition and that the potential harm in screening is likely to be small and mostly due to cost, such as that required to increase the number of dual-energy x-ray absorptiometry (DXA) scanners available for screening.[109] In addition, assuming that the risk versus benefit of therapy for osteoporosis is similar for men and women, the men who are most likely to benefit from screening would be those with a 10-year risk for osteoporotic fracture that is equal to or greater than that for 65-year-old white women who have no additional risk factors.[109] It is important to note, however, that there is insufficient current evidence for assessing the risk versus benefit of screening for osteoporosis in men.

The American College of Physicians (ACP) has similar recommendations for screening of osteoporosis in men, including periodic evaluation of risk factors in older men before age 65 years (particularly men who do not choose to be screened) and obtaining DXA for men at increased risk for the disease who are candidates for drug therapy.[110] Risk factors for osteoporosis in men include the following[110] :

• Age older than 70 years
• Low body weight (body mass index [BMI] < 20 to 25 kg/m ²)
• Greater than 10% weight loss (relative to the usual young or adult weight or weight loss in recent years)
• Physical inactivity
• Corticosteroid use
• Androgen deprivation therapy
• Previous fragility fracture

Like the USPSTF, the ACP recommends further research to assess osteoporosis screening tests in men, to determine whether risk factors for osteoporosis in women also apply to men.[110]

Osteoporosis in men should be treated. However, there has been less drug study for osteoporosis in men compared with that of women.[111] Only zoledronic acid has been studied and has shown a risk reduction of new fractures. In a study of 1199 men with osteoporosis, treatment with zoledronic acid resulted in a 67% reduction in the risk of new vertebral fractures.[111]  Other medications use in the treatment of osteoporosis in men include risedronate, strontium ranelate, teriparatide, and denosumab.[111]

Vertebral fractures from osteoporosis may lead to prolonged immobilization and medication use, which carry a range of complications.[112]

Complications of prolonged immobilization include the following:

• Deep venous thrombosis/pulmonary embolism
• Infections
• Pressure sores
• Decreased muscle strength, 10-15% per week
• Decreased bone mass
• Cardiac effects - postural hypotension, decreased cardiac function
• Gastrointestinal effects - constipation, fecal impaction
• Neurosensory side effects - restlessness, anxiety, depression, fear, rapid mood changes, insomnia, hostility, pain intolerance, impaired intellectual and perceptual functioning

Complications of the medications used to relieve symptoms of vertebral fractures include the following:

• Narcotics - constipation, somnolence, dependence
• Nonsteroidal anti-inflammatory drugs (NSAIDs) - peptic ulcer disease, cardiovascular effects, kidney and liver effects, aspirin-exacerbated respiratory effects
• Muscle relaxants - somnolence, dizziness, anticholinergic effects, weakness

The workup consists of appropriate laboratory studies to look for potential secondary causes of osteoporosis and to determine, if needed, what pharmacologic therapies for osteoporosis might be safe to utilize. Measurements of bone mineral density (BMD) to estimate the risk of fracture are indicated.

Conventional radiography is used for the qualitative and semiquantitative evaluation of osteoporosis; morphometry assesses the presence of fractures.[113] Quantitative imaging methods commonly used are dual-energy x-ray absorptiometry (DXA) and quantitative computed tomography (QCT) scanning.[113] In the United States, current diagnostic and treatment criteria for osteoporosis are based solely on QCT hip and DXA spine or hip T-score measurements.[114, 115]

BMD should be measured at both the posteroanterior (PA) spine and hip in all patients undergoing DXA.[5] Forearm BMD should be measured under the following circumstances:

• Hip and/or spine cannot be measured or interpreted
• Hyperparathyroidism
• Very obese patients (over the weight limit for DXA table)

For information on American College of Radiology (ACR) recommendations for evaluating the appropriateness of BMD measurement tests for osteoporosis in patients at risk of developing this condition, see ACR Appropriateness Criteria for osteoporosis and bone mineral density. For assessment of fracture risk, numerous risk calculators are available for fracture prediction. The Fracture Risk Assessment Tool (FRAX) with BMD and the Garvan Frature Risk Calculator with BMD have the best performance according to areas under the receiver operating characteristic (ROC) curve (AUC).[116]

Children and adolescents

The official position of the International Society for Clinical Densitometry (ISCD) is that “fracture prediction should primarily identify children at risk of clinically significant fractures” (eg, fracture of lower-extremity long bones, vertebral compression fractures, or two or more upper-extremity long-bone fractures).[5] However, densitometric criteria alone should not be used to diagnose osteoporosis in children and adolescents. Rather, such a diagnosis in this population must be based on a low bone mineral content (BMC) or BMD in conjunction with a clinically significant fracture history. Fractures are considered clinically significant[5] if one or more of the following are present:

• Lower-extremity long-bone fracture
• Vertebral compression fracture
• Two or more upper-extremity long-bone fractures
• Low BMC or BMD, defined as a BMC or areal BMD Z-score that is –2.0 or less, adjusted for age, sex, and body size, as appropriate

Laboratory studies are used to exclude secondary causes of osteoporosis and to ensure that the selection of pharmacologic therapy for osteoporosis is appropriate, based on kidney function and serum calcium levels. Baseline studies are summarized in Tables 5 and 6, below.

Table 5. Baseline Laboratory Studies for Underlying Disorders in Osteoporosis (Open Table in a new window)

An important study by Tannenbaum evaluated 173 healthy women (ages 46-87 years) for secondary causes of osteoporosis and found that 55 (32%) had a previously undiagnosed disorder of bone or mineral metabolism.[119] Given that occult disorders are so common in patients with osteoporosis, minimal laboratory screening is indicated in all patients who present with decreased bone mass.

Table 6. Tests for Secondary Causes of Osteoporosis (Open Table in a new window)

Biochemical markers of bone turnover reflect bone formation or bone resorption. These markers (both formation and resorption) may be elevated in high-bone-turnover states (eg, early postmenopausal osteoporosis) and may be useful in some patients for monitoring early response to therapy.

Currently available serum markers of bone formation (osteoblast products) include the following:

• Bone-specific alkaline phosphatase (BSAP)
• Osteocalcin (OC)
• Carboxyterminal propeptide of type 1 collagen (P1CP)
• Aminoterminal propeptide of type 1 collagen (P1NP)

Currently available urinary markers of bone resorption (osteoclast products) include the following:

• Hydroxyproline
• Free and total pyridinolines (Pyd)
• Free and total deoxypyridinolines (Dpd)
• N-telopeptide of type 1 collagen cross-links (NTX-1) (also available as a serum marker)
• C-telopeptide of type 1 collagen cross-links (CTX-1) (also available as a serum marker)

Currently available serum markers of bone resorption include the following:

• Cross-linked C-telopeptide of type 1 collagen (ICTP)
• Tartrate-resistant acid phosphatase 5b (TRAP-5b)
• N-telopeptide of type 1 collagen cross-links (NTX-1) (also available as a urinary marker)
• C-telopeptide of type 1 collagen cross-links (CTX-1) (also available as a urinary marker)

BSAP is nonspecific and can be mildly elevated in patients with fractures. In addition, patients with hyperparathyroidism, Paget disease, or osteomalacia can have elevations of BSAP. Serum OC levels, if high, indicate a high-turnover type of osteoporosis.[120] Elevation of urinary NTX-1 (> 40 nmol bone collagen equivalent per mmol urinary creatine) indicates a high-turnover state.

The International Osteoporosis Foundation (IOF) and the International Federation of Clinical Chemistry (IFCC) Bone Marker Standards Working Group have identified P1NP and CTX-1 in serum to be the reference markers of bone turnover for bone formation and bone resorption, respectively, for the fracture risk prediction and monitoring of osteoporosis treatment.[121]  However, significant controversy still exists regarding the use of these biochemical markers, and concerns have been raised about intra-assay and interassay variability. Further study is needed to determine the clinical utility of these markers in osteoporosis management.

For more information, see Bone Markers in Osteoporosis.

Plain radiography is recommended to assess overall skeletal integrity. In particular, in the workup for osteoporosis, plain radiography may be indicated if a fracture is already suspected or if patients have lost more than 1.5 inches of height (see the following image).

Asymmetric loss in vertebral body height, without evidence of an acute fracture, can develop in patients with osteoporosis. These patients become progressively kyphotic (as shown) over time, and the characteristic hunched-over posture of severe osteoporosis develops eventually.

Obtain radiographs of the affected area in symptomatic patients. Lateral spine radiography can be performed in asymptomatic patients in whom a vertebral fracture is suspected, in those with height loss in the absence of other symptoms, or in those with pain in the thoracic or upper lumbar spine (see the following image). A scoliosis series is useful for detecting occult vertebral fractures.

Severe osteoporosis. This radiograph shows multiple vertebral crush fractures. Source: Government of Western Australia Department of Health.

Radiographic findings can suggest the presence of osteopenia, or bone loss, but cannot be used to diagnose osteoporosis. Osteopenia is suggested by a cortical width that is less than the medullary width. Radiographs may also show fractures or other conditions, such as osteoarthritis, disk disease, or spondylolisthesis.

Plain radiography is not as accurate as BMD testing. Because osteoporosis predominantly affects trabecular bone rather than cortical bone, radiography does not reveal osteoporotic changes until they affect the cortical bone. Cortical bone is not affected by osteoporosis until more than 30% of bone loss has occurred. Approximately 30-80% of bone mineral must be lost before radiographic lucency becomes apparent on radiographs.[122] Thus, plain radiography is an insensitive tool for diagnosing osteoporosis.

Several large prospective studies have shown that BMD measurements of the distal and proximal femur and the vertebral bodies can predict the development of the major types of osteoporotic fractures. BMD has been shown to be the best indicator of fracture risk. According to the National Osteoporosis Foundation (NOF), evaluating BMD on a periodic basis is the best way to monitor bone mass and future fracture risk,[4, 6] although there is controversy about how frequently to measure this.[123]

DXA is currently the criterion standard for the evaluation of BMD.[5, 6] Compared with other screening tools (eg, calcaneal quantitative ultrasonography, the Simple Calculated Osteoporosis Risk Estimation [SCORE]), DXA has been found to be efficacious and cost-effective.[124] DXA is not as sensitive as quantitative computed tomography (QCT) scanning for detecting early trabecular bone loss, but it has comparable costs,[124] it is done on an outpatient basis,[4] and there are no special requirements for performing it. Also, radiation exposure is kept to a minimum.

DXA is used to calculate BMD at the lumbar spine, hip, and proximal femur (see the images below). Densitometric spine imaging can be performed at the time of DXA scanning to detect vertebral fractures. Not all DXA machines are capable of performing vertebral fracture assessment (VFA), but when available, VFA should be considered if the results may influence clinical management of the patient.[125]

Example of a dual energy x-ray absorption (DXA) scan. This image is of the left hip bone. Source: Government of Western Australia Department of Health.

Example of a dual energy x-ray absorption (DXA) scan. This image is of the lumbar spine. Source: Government of Western Australia Department of Health.

Although measurement of BMD at any site can be used to assess overall fracture risk, measurement at a particular site is the best predictor of fracture risk at that site. Whenever possible, the same technologist should perform subsequent measurements on the same patient using the same machine. This method can be used in both adults and children. Factors that may result in a falsely high BMD determination include spinal fractures, osteophytosis, scoliosis, and extraspinal (eg, aortic) calcification.

Bone density data from a DXA are reported as T-scores and Z-scores. The T-score is the value compared to that of control subjects who are at their peak BMD, whereas the Z-score reflects a value compared to that of patients matched for age and sex.[7, 8, 9, 10]

WHO T-score and Z-score criteria

World Health Organization (WHO) criteria define a normal T-score value as within 1 standard deviation (SD) of the mean BMD value in a healthy young adult. Values lying farther from the mean are stratified as follows[9] :

• T-score of –1 to –2.5 SD indicates osteopenia (low bone mass)
• T-score of less than –2.5 SD indicates osteoporosis
• T-score of less than –2.5 SD with fragility fracture(s) indicates severe osteoporosis

For each SD reduction in BMD, the relative fracture risk is increased 1.5-3 times. Of note, about half of osteoporotic fractures occur in women with a T-score greater than –2.5, and the other half occur in those with a T-score lower than –2.5, the WHO’s cutoff for DXA-based diagnosis of osteoporosis.

This diagnostic classification should not be applied to premenopausal women, men younger than 50 years, or children. Instead, Z-scores adjusted for ethnicity or race should be used, with values of –2.0 SD or lower defined as "below the expected range for age" and those above –2.0 SD being "within the expected range for age." The diagnosis of osteoporosis in these groups should not be based on densitometric criteria alone.

International Society of Clinical Densitometry (ISCD) positions

The following are the official positions of the ISCD on peripheral DXA (pDXA)[5] :

• pDXA can be used in postmenopausal women for fracture risk assessment (vertebral and global fragility fracture risk), although its vertebral fracture predictive ability is weaker than central DXA and heel quantitative ultrasonography (QUS); evidence for use in men is insufficient

• The WHO diagnostic classification can be applied only to DXA at the femoral neck, total femur, lumbar spine, and the 33% radius region of interest (located in the distal forearm) measured by DXA or pDXA devices utilizing a validated young-adult reference database

• If central DXA cannot be done, radius pDXA measurements can be used to identify patients in whom pharmacologic treatment should be initiated; the fracture probability, based on both device-specific thresholds and clinical risk factors, should be high in those patients

• pDXA cannot be used to monitor the effects of osteoporosis treatments

Measurements of bone strength

Measurements of bone strength that can be obtained by DXA, with appropriate software, include hip structural analysis (HSA) and trabecular bone scores (TBS). An additional technique for measurement of bone strength, finite element analysis (FEA), can be based on either computed tomography (CT) or DXA .

Hip structural analysis

HSA uses data obtained from DXA examinations to estimate structural properties of the femur. Specifically, estimated parameters such as femoral neck cross-sectional moment of inertia, hip axis length, and cross sectional area parameters can be combined with clinical characteristics (eg, age, weight, ethnicity) to calculate the femoral strength index, which is ultimately an estimate of how well the femur can withstand a direct impact to the greater trochanter.[126]

HSA measurements have been found to correlate well with other measures of bone density such as DXA-derived BMD and quantitative CT[127] but have not consistently demonstrated superiority.[128] Furthermore, the ability of HSA to determine bending strength is limited to the specific plane of the image; comparisons require consistent and correct positioning, which has proven a hindrance to widespread clinical use.[129, 130]

Trabecular bone scores

TBS are another DXA-derived measurement of bone strength. TBS uses “gray-level texture measurements” from two-dimensional DXA scans of the lumbar spine to derive bone strength parameters.[131] TBS may complement standard measures of BMD.[132]

Finite element analysis

Traditional methods of measuring bone density (eg, DXA), while inexpensive and easy to perform, do not account for all the material properties of bone. In fact, many females, and even more males, who sustain hip fractures have BMDs above the osteoporotic threshold.[133] FEA is a relatively new technique for measuring fracture risk that is emerging as a highly accurate tool to evaluate bone strength.

With FEA, three-dimensional renderings of bone created using CT images[134] or DXA[135] are subjected to computer-simulated loads until fracture. This technique for measuring bone strength is mostly used in research settings, but has the potential for future clinical use.[136]

Quantitative computed tomography (QCT) is another method employed to measure  BMD. At the spine, it measures BMD as a true volume density in g/cm3, which is not influenced by bone size. This technique can be used in both adults and children. QCT scanning of the spine is the most sensitive method for diagnosing osteoporosis, because it measures trabecular bone within the vertebral body.[137] At the hip, QCT produces DXA-equivalent T-scores and BMD measures in g/cm2.[114, 115]

QCT scanning may be useful in identifying fractures. It can be used to identify not only the fracture line but also areas of callus formation and sclerosis, consistent with healing fracture. It may also be used for evaluation of metastatic bone disease.

Compared with DXA scanning, QCT has a comparable cost[124] and precision.[114, 138, 139, 140] In addition, as with DXA, no dye injection should be used.[141] QCT is a very sensitive technique when repeated measurements are needed to detect small changes in BMD, and modern three-dimensional (3D) QCT acquisition has a scan time less than 10 seconds for the lumbar spine or proximal femur, and there is no interference by osteophytes.[142, 143] However, QCT requires a higher radiation dose.[143]

Nonetheless, QCT scanning is less commonly used than DXA; based on US Medicare data, about 5% of all BMD assessments are done with QCT scanning. Smaller, rural hospitals may favor QCT scanning, as they often already have a CT scanner for trauma cases and may not be able to afford a DXA machine as well.

International Society of Clinical Densitometry positions

The following are the official positions of the International Society of Clinical Densitometry (ISCD) on QCT of the lumbar spine[5]

• When using single-slice QCT, L1-L3 should be scanned; with 3D QCT, L1-L2 should be scanned

• QCT of the spine can be used to predict vertebral fractures in postmenopausal women, but there is insufficient evidence to recommend spine QCT for spinal fracture prediction in men or hip fracture prediction in both women and men

• Peripheral QCT (pQCT) of the forearm at the ultra-distal radius predicts hip, but not spine, fragility fractures in postmenopausal women; there is lack of sufficient evidence to support this position for men

• Because T-scores by QCT are not equivalent to T-scores based on DXA, the World Health Organization (WHO) diagnostic classification of osteoporosis cannot be used

• If central DXA measurements cannot be obtained, QCT of the spine or pQCT of the radius can be used to identify patients who are appropriate candidates for pharmacologic treatment; fracture probability based on both device-specific thresholds and clinical risk factors should be high in those patients

• QCT of the spine can be used to monitor age-, disease- and treatment-related BMD changes via trabecular BMD of the lumbar spine

The following are the official positions of the ISCD on pQCT of the radius[5] :

• pQCT of the forearm at the ultra-distal radius cannot be used for fracture risk assessment of the spine, but does predict hip fragility fractures in postmenopausal women

• There is insufficient evidence to recommend pQCT for fracture risk prediction in men

• As with QCT of the spine, pQCT of the radius cannot be used to diagnose osteoporosis based on the WHO diagnostic classification

• As with QCT of the spine, pQCT of the radius along with clinical risk factors can be used to initiate pharmacologic treatment if central DXA cannot be obtained

• pQCT measurements of the trabecular and total BMD of the ultra-distal radius can be used to monitor age-related BMD changes

Single-photon emission computed tomography (SPECT) scanning represents a tomographic (CT-like) bone imaging technique that offers better image contrast and more accurate lesion localization than planar bone scanning. It increases the sensitivity and specificity of bone scanning for detection of lumbar spine lesions by 20-50% over planar techniques.

SPECT scanning is helpful when accurate localization of skeletal lesions within large and/or anatomically complex bony structures is required. This localization is possible because SPECT can visualize bony structures that would overlap on planar images (eg, separating vertebral body, facet and pars interarticularis lesions).

Quantitative ultrasonography (QUS) of the calcaneus is a low-cost portable screening tool. It has the advantage of not involving radiation, but it is not as accurate as other imaging methods. Ultrasonography cannot be used for monitoring skeletal changes over time, nor can it be used to monitor the response to treatment, because of its lack of precision.

International Society of Clinical Densitometry positions

The following are the official positions of the ISCD on QUS[5] :

• Bone density measurements from QUS devices should be independently validated; measurements by different devices cannot be directly compared

• The heel is the only validated skeletal site for the clinical use of QUS in osteoporosis management

• Validated calcaneal QUS devices can be used in postmenopausal women to predict hip, vertebral, and global fracture risk, and in men older than 65 years to predict hip and all nonvertebral fractures

• The WHO diagnostic classification cannot be applied to T-scores from QUS measurements

• If central DXA cannot be obtained, calcaneal QUS in combination with clinical risk factors can be used to identify patients in whom pharmacologic treatment should be initiated

• Calcaneal QUS plus clinical risk factors can also be used to identify patients at very low fracture probability in whom no further diagnostic testing is necessary

• QUS cannot be used to monitor the skeletal effects of treatments for osteoporosis

Magnetic resonance imaging (MRI) may be useful in identifying fractures and in the assessment of metabolic bone disease. Using fat-suppression sequences, marrow edema consistent with fracture may be noted as areas of hypointensity on T1-weighted images in association with corresponding areas of hyperintensity on T2-weighted images. MRI is a very sensitive modality and is believed by some to be the diagnostic imaging method of choice in the detection of acute fractures, such as sacral fractures.

MRI can be used to discriminate between acute and chronic fractures of the vertebrae and occult stress fractures of the proximal femur. These osteoporotic fractures demonstrate characteristic changes in the bone marrow that distinguish them from other uninvolved parts of the skeleton and the adjacent vertebrae.

Bone scans assesses the function and tissue metabolism of organs by using a radionuclide (technetium-99m [99m Tc]) that emits radiation in proportion to its attachment to a target structure. This technique detects an increase in osteoblastic activity (as seen in compression fractures).

Images may be obtained in three phases of the bone scanning process (immediate-flow study, immediate static blood pool study, and delayed static study). Acute fractures are visible in all phases of bone scanning and may remain beyond the reference range for up to 2 years.

Bone biopsy can help to exclude underlying pathologic conditions, such as mastocytosis, that may be responsible for presumed osteoporotic fracture. Typically, iliac crest biopsy is performed either in the minor procedure suite or in the operating room.

Tetracycline double labeling is a process used to calculate data on bone turnover. In this procedure, patients are given tetracycline, which binds to newly formed bone. This appears on biopsy samples as linear fluorescence. A second dose of tetracycline is given 11-14 days after the first dose; this appears on a biopsy sample as a second line of fluorescence. The distance between the two fluorescent labels can be measured to calculate the amount of bone formed during that interval, which may potentially indicate that too little bone formation or too much bone resorption is the cause of osteoporosis in a patient. Tetracycline labeling may also help clinicians to test potential therapy (ie, did the treatment slow bone resorption, increase bone formation, or both?) and study other metabolic bone responses.

Histologic examination of osteoporotic bone may reveal generalized thinning of trabeculae and irregular perforation of trabeculae, reflecting unbalanced osteoclast-mediated bone resorption.[73] The following images are of histologic specimens from patients with osteoporosis.

Osteoporosis is defined as a loss of bone mass below the threshold of fracture. This slide (methylmethacrylate embedded and stained with Masson's trichrome) demonstrates the loss of connected trabecular bone.

The bone loss of osteoporosis can be severe enough to create separate bone "buttons" with no connection to the surrounding bone. This easily leads to insufficiency fractures.

Inactive osteoporosis is the most common form and manifests itself without active osteoid formation.

Osteoporosis that is active contains osteoid seams (red here in the Masson's trichrome).

Woven bone arising directly from surrounding mesenchymal tissue.

This image depicts bone remodeling with osteoclasts resorbing one side of a bony trabecula and osteoblasts depositing new bone on the other side.

Osteoclast, with bone below it. This image shows typical distinguishing characteristics of an osteoclast: a large cell with multiple nuclei and a "foamy" cytosol.

In this image, several osteoblasts display a prominent Golgi apparatus and are actively synthesizing osteoid. Two osteocytes can also be seen.

A clinical practice guideline from the American College of Physicians on treatment to prevent fractures in men and women with low bone density or osteoporosis includes six recommendations: two strong recommendations, based on high- or moderate-quality evidence, and four weak ones, based on low-quality evidence.[144] The two strong recommendations are as follows:

• Clinicians should offer pharmacologic treatment to women with known osteoporosis to reduce the risk for hip and vertebral fractures; alendronate, risedronate, zoledronic acid, or denosumab may be used.
• In postmenopausal women, estrogen or estrogen plus progestogen or raloxifene should not be used for the treatment of osteoporosis.

The four weak recommendations are as follows:

• In women with osteoporosis, pharmacologic treatment should last for 5 years; generic drugs should be used when possible.

• Monitoring of bone mineral density (BMD) during the 5 years of treatment in women with osteoporosis is not advised, as evidence suggests that fracture risk may be reduced regardless of BMD changes.

• For women aged 65 and older who have osteopenia and are at high fracture risk, decisions to treat should take into account patient preference, fracture-risk profile, benefits, harms, and price of medications.

• In men with clinically recognized osteoporosis, clinicians should offer bisphosphonate therapy to reduce the risk of vertebral fracture; evidence is lacking on BMD monitoring in men.

Nonpharmacologic preventive measures include modification of general lifestyle factors, such as increasing weight-bearing and muscle-strengthening exercise, which epidemiologic studies have linked to lower fracture rates, and ensuring optimum calcium and vitamin D intake as adjunct to active antifracture therapy.[11]  In addition, potentially treatable underlying causes of osteoporosis such as hyperparathyroidism and hyperthyroidism should be ruled out or treated if detected.

There may be an increased risk of fractures involving adjacent vertebrae if therapies including vertebroplasty or kyphoplasty were used in the management of painful osteoporotic fractures[145, 146]

A 2008 literature review suggested that the use of "reminders plus education targeted to physicians and patients" can lead to increased BMD testing and greater use of osteoporosis medications.[147] In addition, a physician reminder in conjunction with a patient risk assessment strategy can result in a reduction in patient fractures and an increase in osteoporosis therapy. The authors concluded that multicomponent tools aimed at doctors and patients may support clinical decision making in the management of osteoporosis.

A 2009 study indicated that the use of a case manager for the treatment of patients with hip fractures can lead to more frequent use of appropriate osteoporosis treatment and may result in fewer fractures, increased life expectancy, and significant health-care cost savings.[14]

In patients who have experienced an osteoporotic fracture, the first goal of rehabilitation is to control pain. Spinal compression fractures can be extremely painful and can cause short- and long-term morbidity. Oral analgesics can be implemented. Calcitonin may rarely help acute pain associated with acute osteoporotic vertebral compression fractures.[148] Nonpharmacologic pain-relieving modalities such as moist hot packs and transcutaneous electrical nerve stimulation should also be considered. Patients receiving narcotic analgesics for acute pain control require careful monitoring for adverse effects of these agents: constipation, urinary retention, and respiratory depression. Orthotics may be used to decrease the flexion forces to prevent the worsening of kyphosis and to reduce the pressure on the fracture site in the acute phase of disease.[149, 150]

Currently, no treatment can completely reverse established osteoporosis. Early intervention can prevent osteoporosis in most people. For patients with established osteoporosis, medical intervention can halt its progression. If secondary osteoporosis is present, treatment for the primary disorder should be provided. Therapy should be individualized based on each patient’s clinical scenario, with the risks and benefits of treatment discussed between the clinician and patient.[109, 151]

Patients identified as at risk for osteoporosis (including children and adolescents) should undergo preventive measures, including adequate calcium intake, vitamin D intake, and exercise. Patients should be counseled to avoid tobacco and excessive alcohol use.

Protective measures should be taken in patients who must take glucocorticoids for other medical conditions. These include using the minimum effective dose of glucocorticoid and discontinuing the drug as soon as possible. The American College of Rheumatology provides recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis, which were updated in 2017. Recommendations include optimizing calcium and vitamin D supplementation, lifestyle modifications, and fracture risk stratification for all adults on long-term glucocorticoid treatment (≥2.5 mg/day prednisone for ≥3 months).[12]  Further recommendations regarding pharmacological therapy as dictated by fracture risk stratification for prevention of glucocorticoid-induced osteoporosis (GIOP) are discussed below in Prevention of Osteoporosis.  

Bisphosphonates

Bisphosphonates are the most commonly used agents for osteoporosis. Oral and intravenous options are available.

Alendronate

Alendronate (Fosamax) is approved for the treatment of osteoporosis in men, in postmenopausal women, and in patients with glucocorticoid-induced osteoporosis. It has been shown to increase spine and hip bone mineral density in postmenopausal women. Well-conducted controlled clinical trials indicate that alendronate reduces the rate of fracture at the spine, hip, and wrist by 50% in patients with osteoporosis.

The treatment dose of alendronate is 70 mg/week, to be taken sitting upright with a large glass of water at least 30 minutes before eating in the morning. Alendronate is also available in combination with cholecalciferol (vitamin D3). The combination of alendronate with vitamin D3 (Fosamax Plus D) is indicated for the treatment of osteoporosis in men to increase bone mass.

The oral bioavailability of alendronate is drastically reduced when taken with food, even black coffee or orange juice alone.[152]  In addition, the results of a population-based, national register–based, open cohort study of 38,088 patients suggest that elderly patients who use proton pump inhibitors in conjunction with alendronate have a dose-dependent loss of protection against hip fracture.[153]

Risedronate

Other oral bisphosphonates include risedronate (Actonel) or risedronate delayed-release (Atelvia), given daily, weekly, or monthly. It is also available as a combination product with calcium as risedronate/calcium carbonate (Actonel with Calcium). Risedronate reduced vertebral fractures by 41% and nonvertebral fractures by 39% over 3 years.[154]

Ibandronate

Ibandronate (Boniva) is another bisphosphonate that can be given orally once a month and is also available as an intravenous formulation that is given every 3 months. Intravenous bisphosphonates are excellent choices for patients intolerant of oral bisphosphonates or for those in whom adherence is an issue. However, ibandronate has not shown efficacy in nonvertebral fractures in clinical trials.

Zoledronic Acid

Zoledronic acid (Reclast) is a once-yearly intravenous infusion approved for the treatment of osteoporosis in men, in postmenopausal women, and in patients with glucocorticoid-induced osteoporosis.[155]  Zoledronic acid is the most potent bisphosphonate available. It increases BMD at the spine by 4.3-5.1% and the hip by 3.1-3.5%, as compared with placebo. Over 3 years, it reduces the incidence of spine fractures by 70%, hip fractures by 41%, and nonvertebral fractures by 25% in postmenopausal women. A similar effect on vertebral fractures has been shown in men. A randomized, 2-year trial of men with osteoporosis found that once-yearly zoledronic acid infusions significantly decreased the risk of new morphometric vertebral fractures by 67%.[156]

A randomized, placebo-controlled, double-blind trial suggested that a once-yearly 5-mg dose of IV zoledronic acid increases bone mass in men within 90 days of hip fracture repair; similar increases were noted in women.[157]

Bisphosphonates and bone turnover

Over time, bisphosphonate therapy decreases bone turnover and, at very high levels in animals, decreases bone strength and resilience. Some limited reports, including that by Odvina et al, describe patients on long-term bisphosphonate therapy developing transverse stress fractures; biopsy specimens of these individuals have suggested extremely low turnover states in some of them.[158]

Alendronate and risedronate inhibit bone resorption at doses 10-fold lower than those reducing osteoclast number. Thus, suppression of bone resorption with these agents is independent of their effects on apoptosis.[159]

Complications of bisphosphonate therapy, treatment length, and drug holidays

In 2011, the US Food and Drug Administration (FDA) updated the prescribing information for zoledronic acid to provide improved information regarding the risk of kidney failure. Acute kidney injury requiring dialysis and fatal outcomes have been reported to the FDA following the use of zoledronic acid. The drug is contraindicated in patients with moderate to severe renal impairment (ie, creatinine clearance < 35 mL/min) or evidence of acute renal impairment. Risk for acute kidney injury is also increased by the following[160] :

• Coadministration of zoledronic acid with nephrotoxic or diuretic medications
• Severe dehydration before or after administration
• Advanced patient age

In 2012, the FDA made safety labeling changes for bisphosphonates, including zoledronic acid, to advise of the risk for atypical subtrochanteric and diaphyseal femoral fractures in patients who have received bisphosphonate therapy, including zoledronic acid. These fractures occur with minimal or no trauma and may present as groin pain weeks to months after fracture. The FDA also includes a safety warning for bisphosphonates, including zoledronic acid, regarding the risk for osteonecrosis of the jaw (ONJ).[161]  Atypical femur fractures and ONJ are rare events in patients on long- term antiresportive agents, including bisphosphonates or denosumab, when used in the treatment of osteoporosis.

The incidence of ONJ in patients on antiresportive therapy for osteoporosis is estimated to be between 1 in 10,000 and 1 in 100,000 per year of use; this risk is only very minimally, if at all, increased compared with the general population. In contrast, the use of IV bisphosphonates and denosumab in cancer patients to reduce complications of metastatic cancer results in the administration of substantially higher cumulative doses (due to the increased dosage used for these indications); therefore, atypical femoral fractures and ONJ are more commonly seen when IV bisphosphonates or denosumab are used as part of cancer treatment.[162]

In 2012, the FDA made safety labeling changes for zoledronic acid to warn against the following adverse reactions[161] :

• Acute phase reaction within 3 days of zoledronic acid administration: symptoms include pyrexia, fatigue, bone pain and/or arthralgias, myalgias, chills, and influenza-like illness; symptoms usually resolve within 3 days of onset but can take 7-14 days to resolve, and some symptoms may persist for longer 

• Hypersensitivity reactions presenting as bronchospasms; interstitial lung disease (ILD) with positive re-challenge

The limited trial data available regarding long-term treatment with bisphosphonates has raised questions about the optimal length of treatment with these medications.[163] This issue has become more important, given newly recognized complications of bisphosphonate use, including ONJ[164] and atypical (subtrochanteric or femoral shaft) femur fractures.

Some studies have sought to clarify the true risks of complications in patients receiving bisphosphonates. A Canadian study by Park-Willie et al found the estimated absolute risk of a subtrochanteric or femoral shaft fracture to be low in 52,595 women with at least 5 years of bisphosphonate therapy (0.13% during the subsequent year and 0.22% within 2 years).[165]  Longer use of bisphosphonates has been shown to increase risk of atypical femoral fractures.[166]  Overall, a patient’s risk of fracture can be used to help guide length of treatment. Patients at high risk may be continued on bisphosphonates after 5 years; however, in some patients, especially those with a lower risk of fracture, bisphosphonate treatment may be stopped for a period with subsequent reassessment of fracture risk, often termed a "drug holiday."[167]

The AACE recommends that if fracture risk is no longer high or the patient has remained fracture free, clinicians should consider a drug holiday after 5 years of bisphosphonate treatment; treatment should continue up to an additional 5 years if fracture risk remains high. For high fracture risk patients, a drug holiday may be considered after 6-10 years of treatment. For zoledronate, consider a bisphosphonate holiday after 3 years in high-risk patients or until fracture risk is no longer high, and continue for up to 6 years in very-high risk patients.[11]

The ending of a bisphosphonate holiday should be based on individual patient circumstances. BMD and bone turnover markers should be monitored, and treatment should be restarted when the density declines substantially, bone turnover markers increase, or an increase in fracture risk or fracture occurs.[11]

In 2016, the American Society for Bone and Mineral Research published guidelines on long-term bisphosphonate treatment that included the following recommendations[168] :

• After 5 years of oral bisphosphonates or 3 years of intravenous bisphosphonates, reassessment of risk should be considered.
• In women at high risk (eg, older women, those with a low hip T-score or high fracture risk score, those with previous major osteoporotic fracture, or those who fracture on therapy), continuation of treatment for up to 10 years (oral) or 6 years (intravenous), with periodic evaluation, should be considered.
• The risk of atypical femoral fracture, but not ONJ, clearly increases with the duration of bisphosphonate therapy, but such rare events are outweighed by vertebral fracture risk reduction in high-risk patients.
• For women not at high fracture risk, a drug holiday of 2 to 3 years can be considered after 3 to 5 years of bisphosphonate treatment.

Selective estrogen receptor modulators

Selective estrogen receptor modulators (SERMs) are considered to provide the beneficial effects of estrogen while mitigating the potentially adverse outcomes.

Raloxifene

Raloxifene (Evista) is a SERM indicated for the treatment and prevention of osteoporosis in postmenopausal women. The usual dose is 60 mg given orally daily. It can also be given in combination with calcium and vitamin D. It is the first SERM studied for breast cancer prevention, and it decreases bone resorption through actions on estrogen receptors.

Raloxifene has been shown to prevent bone loss, and data in women with osteoporosis have demonstrated that this agent causes a 35% reduction in the risk of vertebral fractures. It has also been shown to reduce the prevalence of invasive breast cancer. However, raloxifene is not without risk; it has been shown to increase the incidence of deep vein thrombosis, stroke, and hot flashes.

Raloxifene may be most useful in younger postmenopausal women without severe osteoporosis. In 601 postmenopausal women who had daily therapy with raloxifene, BMD was increased, serum concentrations of total low-density lipoprotein cholesterol were lowered, and the endometrium was not stimulated.

Pooled mortality data from large clinical trials of raloxifene (60 mg/day) were analyzed by Grady et al in 2010. When compared with placebo, all-cause mortality was 10% lower in older postmenopausal women receiving raloxifene. The primary reduction was in noncardiovascular, noncancer deaths.[169]  However, in contrast, the FDA has advised a black box warning on raloxifene for increased risk of venous thromboembolism and death from stroke. Increased risk of deep vein thrombosis, pulmonary embolism, and death due to stroke have been seen in trials with raloxifene and this must be weighed against potential benefit to patient for osteoporosis when considering prescribing raloxifene or other SERMs.

Bazedoxifene/conjugated estrogens

The combination product of bazedoxifene, a SERM, and conjugated estrogens (CEs) is approved by the FDA for prevention of osteoporosis and treatment of vasomotor symptoms in postmenopausal women. Combining a SERM with CEs lowers the risk of uterine hyperplasia caused by estrogens. This eliminates the need for a progestin and its associated risks (eg, breast cancer, myocardial infarction, venous thromboembolism).

In clinical trials, this combination decreased bone turnover and bone loss in postmenopausal women at risk for osteoporosis. Bone mineral density increased significantly more with all bazedoxifene/CE doses compared with placebo at the lumbar spine and total hip and with most bazedoxifene/CE doses compared with raloxifene at the lumbar spine.[170]

Parathyroid hormone analogues

Teriparatide

Teriparatide (Forteo) is a recombinant human parathyroid hormone (1-34) (PTH [1-34]) that acts as an anabolic agent for the treatment of osteoporosis. It is indicated for the treatment of women with postmenopausal osteoporosis who are at high risk of fracture, who have been intolerant of previous osteoporosis therapy, or in whom osteoporosis treatment has failed to increase bone mass. It is indicated in men with idiopathic or hypogonadal osteoporosis who are at high risk of fracture, who have been intolerant of previous osteoporosis therapy, or in whom osteoporosis therapy has failed. Teriparatide is also approved for the treatment of patients with glucocorticoid-induced osteoporosis.

Before treatment with teriparatide, levels of serum calcium, PTH, and 25(OH)D need to be monitored. Teriparatide cannot be given for more than 2 years total in a lifetime due to concerns for increased risk of osteosarcoma; higher incidence of osteosarcoma was seen with high doses in animal studies. However, evidence to show an increased risk of osteosarcoma in humans receiving therapeutic doses of teriparatide has not been obtained.[171]  Contraindications include the following:

• Pre-existing hypercalcemia
• Severe renal impairment
• Pregnancy
• Breast-feeding mothers
• History of bone metastases or skeletal malignancies
• Increased baseline risk for osteosarcoma, including but not limited to Paget disease, unexplained elevated alkaline phosphatase level, or prior external beam or implant radiation therapy
• Children and young adults with open epiphyses or prior radiotherapy of the skeleton ^[172]
• Monoclonal gammopathies of undetermined significance (MGUS) ^[173]

When PTH is given continuously, both osteoclastic and osteoblastic turnover increase, leading to a net loss of bone. However, intermittent subcutaneous administration of PTH in a dosage of 20 mcg/day has been demonstrated to induce a very active anabolic phase, with bone mass increasing up to 13% over 2 years in the spine and to a lesser degree in the hip.[174, 175, 176]

Indications for PTH in men and women are a bone density decline while on bisphosphonate therapy, bone density stabilization while on extremely low-level bisphosphonate therapy, a fracture occurring while on bisphosphonate therapy, or a very low initial bone turnover rate for which an anabolic effect is clearly warranted. Teriparatide should be considered in younger and older postmenopausal women with severe osteoporosis.

Most studies with PTH have been performed on women. The medication decreases the risk of vertebral and nonvertebral fractures to the same extent as bisphosphonates. Teriparatide is given for a maximum of 2 years, after which time the gains in BMD achieved with PTH are secure and can even be augmented with bisphosphonate therapy; otherwise, the BMD slowly deteriorates to pretreatment levels.[177]

According to Finkelstein et al, initial studies using a combination of concurrent PTH and bisphosphonate therapy showed decreased benefit compared with therapy with either agent alone; therefore, the general recommendation is that these drugs be given separately and in sequence.[178]

A study by Cosman and colleagues challenged this conclusion by giving 3-month-on, 3-month-off pulses of teriparatide while the patients were on weekly alendronate; BMD in the spine increased above that of the alendronate-only arm.[179] This pulsed regimen appears to take advantage of the 3- to 4-month so-called anabolic window, in which the markers of bone formation rise more quickly than the markers of bone resorption.

Studies in women by Deal et al and Ste-Marie et al have shown that the concurrent use of estrogen or raloxifene can enhance the bone-forming effects of teriparatide.[180, 181] Data on the use of PTH in men are much more limited, but its efficacy appears to be relatively comparable.

In a randomized, controlled trial (DATA), 94 osteoporotic postmenopausal women were randomized to take 24 months of teriparatide or denosumab alone, or teriparatide and denosumab in combination. Those women taking teriparatide and denosumab in combination had increased BMD after 12 months. The 12-month changes in posterior-anterior lumbar spine, femoral neck, and total hip BMD in the combination-therapy group (9.1%, 4.2% and 4.9%, respectively) were greater than those in the groups receiving only teriparatide (6.2%, 0.8% and 0.7%, respectively) or only denosumab (5.5%, 2.1% and 2.5%, respectively).[182]  

As an extension to this study (DATA-Switch), women originally assigned to teriparatide received denosumab after 24 months and those originally assigned to denosumab received teriparatide. Switching from teriparatide to denosumab yielded progressive BMD increases, whereas switching from denosumab to teriparatide resulted in progressive or transient bone loss.[183]  Given those findings, using teriparatide early in the treatment course before instituting other therapies when severe osteoporosis is diagnosed is preferred.

In a retrospective analysis of the data from the Fracture Prevention Trial and the Multiple Outcomes of Raloxifene Evaluation trial, Bouxsein et al found that teriparatide reduced fracture risk to a greater extent than raloxifene in postmenopausal osteoporotic women. Compared with placebo, teriparatide reduced the risk of any new fractures by 72%, new adjacent fractures by 75%, and new nonadjacent vertebral fractures by 70%. Raloxifene reduced the risks by 54%, 54%, and 53%, respectively.[184]

A double-blind, double-dummy trial by Kendler et al found that in postmenopausal women with severe osteoporosis, the risk of new vertebral and clinical fractures was significantly lower in patients receiving teriparatide than in those receiving risedronate. Study subjects had experienced at least two moderate or one severe vertebral fracture and had a BMD T-score of -1.50 or less. They were randomly assigned to receive teriparatide (daily injections of 20 μg) plus oral weekly placebo or risedronate (35 mg orally once weekly) plus daily injections of placebo for 24 months.[185]

At 24 months, new vertebral fractures had occurred in 28 (5.4%) of 680 patients in the teriparatide group and 64 (12.0%) of 680 patients in the risedronate group (hazard ratio [HR] 0.44, 95% confidence index [CI] 0.29-0.68; P < 0·0001). Clinical fractures occurred in 30 (4.8%) of 680 patients in the teriparatide group compared with 61 (9.8%) of 680 in the risedronate group (hazard ratio 0.48, 95% CI 0.32-0.74; P=0.0009).[185]

Use of teriparatide for atypical fractures has not been studied in large randomized controlled trials due to the small numbers of atypical fractures. Gomberg et al reported a case of successful healing of bilateral subtrochanteric stress fractures in a postmenopausal woman who had used a bisphosphonate for 13 years.[186] A small case series showed that teriparatide may have potential in promoting healing of atypical fractures with radiolucent line in an incomplete fracture.[187]

For ONJ, teriparatide may be a useful adjunctive therapy. Three cases have been reported in which teriparatide has been used successfully in patients with bisphosphonate-associated ONJ.[188, 189, 190]

Abaloparatide

Another PTH analogue, abaloparatide (Tymlos), was approved by the FDA in 2017 for women and in 2022 for men. It is indicated for treatment of postmenopausal women with osteoporosis or to increase bone density in men at high risk for fracture, defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients with failure of or intolerance to other available osteoporosis therapy. Approval in women was based on results at 18 months from the Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) trial[191] and first 6 months of the ACTIVExtend trial.[192]  Approval in men was supported by the Abaloparatide Treatment of Men (ATOM phase 3 study).[193]  

In the ACTIVE trial of more than 2000 women, subcutaneous abaloparatide was associated with significant reductions in the relative risk for new vertebral fractures (86% reduction) and nonvertebral fractures (43% reduction) compared with placebo. The absolute risk reductions were 3.6% and 2.0%, respectively. The benefits were evident regardless of age, years since menopause, presence or absence of prior fracture (vertebral or nonvertebral), and BMD at baseline.[191]

In the ACTIVExtend trial, roughly 1100 patients who had completed 18 months of abaloparatide or placebo in ACTIVE received open-label alendronate for up to 24 additional months. Data from the first 6 months of ACTIVExtend showed improved BMD and reduced fracture risk throughout the skeleton.[192]

A study performed by an Austrian group using PTH 1-84 to treat pelvic fractures in postmenopausal women with osteoporosis demonstrated that this anabolic agent has the ability to both increase the rate of union and enhance the speed of the process. In addition to improved fracture healing, treatment with PTH 1-84 was also associated with a significant decrease of pain and improved function over the placebo arm. This clinical study supports the extensive animal data that predicted a clear role for PTH in fracture repair.[194]  

The ATOM study in men showed an increase from baseline in mineral density at 12 months of 8.5% and 1.2% in the abaloparatide and placebo groups, respectively (p < 0.0001).[193]   

Contraindications to abaloparatide are similar to those for teriparatide. A Black Box warning regarding increased risk of osteosarcoma, based on studies in rats, was removed in December 2021; however, use of abaloparatide should be avoided in patients with increased risk of osteosarcoma, and use of the drug for more than 2 years during a patient’s lifetime is not recommended.

Romosozumab

Romosozumab (Evenity) is a monoclonal antibody that binds with and inhibits sclerostin, and thus both increases bone formation and decreases bone resorption. It was approved by the FDA in 2019 for treatment of osteoporosis in postmenopausal women who are at high risk for fracture. It has been shown to reduce vertebral fracture rates in postmenopausal women with osteoporosis.[195, 196, 197]

In the Fracture Study in Postmenopausal Women With Osteoporosis (FRAME), a phase 3 randomized trial in 7180 postmenopausal women who had a T score of -2.5 to -3.5 at the total hip or femoral neck, 1 year of treatment with romosozumab reduced vertebral fracture rates by 73% compared with placebo. A further reduction in vertebral fracture risk occurred in the second year following transition to denosumab.[195, 197]

Romosozumab is also being investigated in men with osteoporosis. In the BRIDGE clinical trial, spine and hip BMD significantly improved following romosozumab for 12 months compared with placebo.[198]

In a randomized, controlled trial of 4093 postmenopausal women with osteoporosis and a fragility fracture, a higher rate of adjudicated serious cardiovascular events (a composite endpoint including cardiac ischemic events, cerebrovascular events, heart failure, death, noncoronary revascularization, and peripheral vascular ischemic event not requiring revascularization) was seen in the romosozumab group (2.5%) compared with the alendronate group (1.9%), although the increased risk only reached statistical significance for cardiac ischemic events (0.8% versus 0.3%; odds ratio 2.65 with 95% CI 1.03 to 6.77).[199]  

Romosozumab carries a black box warning regarding increased risk of myocardial infarction, stroke, and cardiovascualr death. Romosozumab should not be initaited in patients who have had a myocardial infarction or stroke within the preceding year, and cardiovascular risk profile must be considered before initiating romosozumab. In patients who experience a myocardial infarction or stroke during therapy, romosozumab should be discontinued.

Denosumab

Denosumab (Prolia) is a humanized monoclonal antibody directed against the receptor activator of the nuclear factor–kappa B ligand (RANKL), which is a key mediator of the resorptive phase of bone remodeling.[181] Denosumab decreases bone resorption by inhibiting osteoclast activity. Denosumab was approved by the FDA in 2010. It has shown benefit in cancer patients, patients with postmenopausal osteoporosis, and men with low BMD.[200, 201, 202]  The approved dosage is 60 mg given subcutaneously every 6 months.

Denosumab may be considered in certain patients with renal insufficiency, as impaired kidney function does not significantly affect the metabolism or excretion of the drug.[203]

In 2018, denosumab was approved for treatment of glucocorticoid-induced osteoporosis (GIOP) in men and women at high risk of fracture who are either initiating or continuing systemic glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and who are expected to remain on glucocorticoids for at least 6 months. Patients are considered at high risk of fracture if they have a history of osteoporotic fracture, multiple risk factors for fracture, or failed or cannot tolerate other available osteoporosis therapy.

Approval for use in GIOP was based on an international phase 3 study in which denosumab proved more effective than the bisphosphonate risedronate for increasing BMD at the lumbar spine. In patients who had been on steroids for at least 3 months (n=505), the change from baseline in BMD at 12 months was 4.4% with denosumab versus 2.3% with risedronate (P < 0.0001); in those who had started steroids less than 3 months previously (n=290), the change was 3.8% vs 0.8% (P < 0.0001).[204]

In postmenopausal women with osteoporosis, denosumab reduces the incidence of vertebral, nonvertebral, and hip fractures.[205]  Denosumab also increases bone mass in men at high risk for fracture who are receiving androgen deprivation therapy for nonmetastatic prostate cancer,[206]  and in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer. 

A meta-analysis of 10 randomized, controlled trials concluded that denosumab improved BMD significantly more than bisphosphonate treatment at the lumbar spine, total hip, and femoral neck at 12 and 24 months. However, only 1 of the 10 studies demonstrated greater osteoporotic fracture reduction with denosumab treatment.[207]

In patients with multiple myeloma or bone metastases from breast cancer, a single subcutaneous dose of denosumab decreases bone turnover markers within 1 day, and this effect is sustained through 84 days at higher doses.[200] Denosumab has been shown to increase BMD and decrease bone resorption in postmenopausal women with osteoporosis over a 12-month period. Because the overactivity of RANKL is a major factor in bone loss in patients with autoimmune and inflammatory disorders, such as ulcerative colitis, denosumab may become first-line therapy for these patients.[208]  Denosumab in combination with teriparatide has been shown to increase BMD more than either drug alone,[209]  although combination therapy with osteoporosis medications is not currently recommended in clinical practice.

Denosumab has uniquely been associated with rebound lumbar vertebral fractures after denosumab discontinuation. These vertebral fractures are often multiple and occur within months of the time that the next dose of denosumab would be due for administration.[210]  For this reason, denosumab should be continued indefinitely or followed by bisphosphonate therapy, if not contraindicated.

Calcitonin

Calcitonin salmon (Fortical, Miacalcin) is a hormone that decreases osteoclast activity, thereby impeding postmenopausal bone loss. It is indicated for the treatment of women who are more than 5 years post menopause and have low bone mass relative to healthy premenopausal women. Calcitonin salmon is not considered a first-line therapy for osteoporosis, and should be reserved for patients who refuse or cannot tolerate bisphosphonates or in whom bisphosphonates are contraindicated. It is recommended in conjunction with adequate calcium and vitamin D intake to prevent the progressive loss of bone mass. It is available as an injection and as an intranasal spray. The intranasal spray is delivered as a single daily spray that provides 200 IU of the drug. The drug can be delivered subcutaneously, but this route is rarely used.

Results from a single controlled clinical trial indicate that calcitonin may decrease osteoporotic vertebral fractures by approximately 30%. In the first 2 years, calcitonin has been found to increase spinal bone mineral density (BMD) by approximately 2%. Calcitonin also has  analgesic properties. However, calcitonin lacks data showing a reduction in nonvertebral fracture rates.

In 2013, an FDA post-marketing review was prompted after studies showed increased risk of malignancies in calcitonin-treated patients. In a meta-analysis of 21 randomized, controlled clinical trials with calcitonin salmon (nasal spray or investigational oral formulations), the incidence of malignances in calcitonin-treated patients was 4.1%, versus 2.9% in placebo-treated patients. The data were not sufficient for further analysis by specific malignancies and a definitive causal relationship between calcitonin use and malignancies could not be established. The FDA has recommended that health care professionals assess a patient’s need for osteoporosis therapy as well as benefits and risk of available treatments.[211]

Calcitonin is no longer widely used for treatment of osteoporosis.[144]   Common side effects of nasally administered calcitonin include nasal discomfort, rhinitis, irritation of nasal mucosa, and occasional epistaxis. Nausea, local inflammatory reactions at the injection site, sweating, and flushing are side effects noted with parenteral use.

Hormone replacement therapy

Hormone replacement therapy (HRT) was once considered a first-line therapy for the prevention and treatment of osteoporosis in women. Although HRT is not currently recommended for the treatment of osteoporosis, it is important to mention because many osteoporosis patients in a typical practice still use it for controlling postmenopausal symptoms.

The American College of Physicians concluded that moderate-quality evidence showed that estrogen treatment did not reduce fracture rates in postmenopausal women with established osteoporosis.[144] Data from the Women's Health Initiative indicated that HRT can reduce fractures.[212] However, the results of the Women's Health Initiative were distressing with respect to the adverse outcomes associated with combined estrogen and progesterone therapy (eg, risks for breast cancer, myocardial infarction, stroke, and venous thromboembolic events) and estrogen alone (eg, risks for stroke and venous thromboembolic events).

Other agents

Strontium ranelate is approved for the treatment of osteoporosis in some countries in Europe. It reduces the risk of both spine and nonvertebral fractures.[213, 214] Strontium is not approved for the treatment of osteoporosis in the United States.

Adequate calcium and vitamin D intake are important in persons of any age, particularly in childhood as the bones are maturing, and are essential in the prevention and treatment of osteoporosis. Vitamin D is increasingly being recognized as a key element in overall bone health, calcium absorption, balance (eg, reduction in risk of falls),[215] and muscle performance. Patients who ingest inadequate amounts of vitamin D and calcium in their diet should not receive additional oral supplements.

Good dietary sources of calcium include dairy products, sardines, nuts, sunflower seeds, tofu, vegetables such as turnip greens, and fortified food such as orange juice. Good dietary sources of vitamin D include eggs, liver, butter, fatty fish, and fortified food such as milk and orange juice. See the National Osteoporosis Foundation Website for further calcium and vitamin D recommendations.

The goal of the current recommendations for daily calcium intake is to ensure that individuals maintain an adequate calcium balance. Current recommendations from the American Association of Clinical Endocrinologists (AACE) for daily calcium intake are as follows[11] :

• Age 0-6 months: 200 mg/day
• Age 6-12 months: 260 mg/day
• Age 1-3 years: 700 mg/day
• Age 4-8 years: 1000 mg/day
• Age 9-18 years: 1300 mg /day
• Age 19-50 years: 1000 mg/day
• Females Age 51 years and older: 1200 mg/day
• Males Age 51-70: 1000 mg/day
• Males Age 71 and older: 1200 mg/day

The Institute of Medicine (IOM) has issued recommendations for calcium and vitamin D daily intake in older adults. For women older than 50 years, the IOM recommended 1200 mg/day of calcium. The IOM recommended 1000 mg/day of calcium for men 51-70 years of age and 1200 mg/day for men over 70. For both sexes, the recommended upper level was 2000 mg/day.[216]

For both women and men, the recommended daily dietary allowance of vitamin D was 600 IU from age 51-70 and 800 IU for after age 70, with a recommended maximum of 4000 IU. Amid considerable controversy, the IOM also stated that the evidence supported a role for vitamin D and calcium in bone health, but not in other conditions.[216]

The minimum daily requirement of vitamin D in patients with osteoporosis is 800 IU of cholecalciferol. Many patients require higher levels (continuously or for a short period) to be considered vitamin D replete, which is defined as a serum 25-hydroxyvitamin D level of at least 32 ng/mL.

Alcohol and anorexia nervosa can interfere with nutrition. Excessive alcohol intake can interfere with calcium balance by increasing PTH production and by inhibiting the enzymes that convert inactive vitamin D to its active form; in addition, alcohol can result in hormonal deficiencies and can increase the tendency for falls. Poor nutritional states, such as in anorexia nervosa,[217] have been strongly associated with bone loss. Nutritional and endocrine factors contribute to bone loss; in particular, low estrogen states, which result from low body weight, result in significant bone loss.

Calcium and vitamin D supplementation

Commonly used calcium supplements include calcium carbonate and calcium citrate. Calcium carbonate is generally less expensive and is recommended as a first choice option. Calcium carbonate has better absorption with food, as opposed to calcium citrate, which is better absorbed in the fasting state. Also, fewer tablets are needed with calcium carbonate than with calcium citrate.

Vitamin D is available as ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). Vitamin D is metabolized to active metabolites. These metabolites promote the active absorption of calcium and phosphorus by the small intestine, elevating serum calcium and phosphate levels sufficiently to permit bone mineralization. Ergocalciferol, the form mostly used in supplements and fortified foods, is absorbed with similar efficiency to cholecalciferol, the main dietary form, with similar effects on suppression of PTH.

Calcium and vitamin D studies

A meta-analysis suggested that supplementation with a combination of calcium and vitamin D can reduce fracture risk.[218] Another meta-analysis of 12 double-blind, randomized, controlled trials for nonvertebral fractures and eight trials for hip fractures reported that nonvertebral fracture prevention with vitamin D was dose dependent and that a higher dose (> 400 IU/d) reduced fractures by at least 20% for individuals aged 65 years or older.[219] However, a longitudinal and prospective cohort study concluded that gradual increases in dietary calcium intake did not further reduce fracture risk or osteoporosis in women.[220]

Another meta-analysis concluded that vitamin D alone is not effective in preventing fractures, but vitamin D given together with calcium reduced hip fractures and total fractures, and possibly vertebral fractures.[221] The conclusions were based on seven large studies that were randomized with at least one intervention arm in which vitamin D was given and included analysis of fractures as an outcome and at least 1000 participants.

More information is needed regarding risks associated with long-term calcium supplementation. Dietary calcium intake has not been associated with an increased risk of cardiovascular events.[222] Additionally, some[223] but not all[224] studies suggest an increased risk of nephrolithiasis with calcium and vitamin D supplements, but not with calcium ingested in the diet.[225]

Physical therapy

Physical therapy focuses on improving a patient's strength, flexibility, posture, and balance to prevent falls and maximize physical function.[226, 227] Postural retraining is key in this population. Spinal bone mineral density (BMD) is directly correlated with the strength of the back extensors; therefore, maintaining and strengthening the back extensors should be emphasized.[228] In studies by Sinaki and colleagues, strengthening the back extensor muscles reduced kyphosis and decreased the risk of sustaining vertebral compression fractures.[229, 230]

As soon as the course of therapy allows, weight-bearing exercises should be initiated. Regular weight-bearing exercises are essential for the maintenance of bone mass[65] and should be encouraged in all patients, including children and adolescents (to strengthen the skeleton during the maturation process). Exercise also improves agility and balance, thereby reducing the risk of falls.

Occupational therapy

Training in the performance of activities of daily living (ADLs) and in the proper use of adaptive equipment are essential to the prevention of future falls.[227] Home modification focuses on reducing the risk of falling by installing handrails and grab bars in hallways, stairs, and bathrooms. The use of a shower chair, tub bench, and adaptive bathing devices also can be beneficial. The application of nonskid tape to steps (indoors and outdoors), as well as the removal of throw rugs, may improve home safety.

Aerobic low-impact exercises, such as walking and bicycling, generally are recommended. During these activities, ensure that the patient maintains an upright spinal alignment. Sinaki and Mikkelsen showed that exercises that place flexion forces on the vertebrae tend to cause an increase in the number of vertebral fractures in patients.[228]

Proper therapy for osteoporosis includes 3-5 sessions per week of weight-bearing exercises, such as walking or jogging, with each session lasting 45-60 minutes. The patient should be instructed in a home-exercise program that incorporates the necessary elements for improving posture and overall physical fitness.

In postmenopausal women, impact exercises can increase BMD in the hip and spine. Chien et al examined the efficacy of a 24-week aerobic exercise program consisting of treadmill walking followed by stepping exercises in osteopenic postmenopausal women aged 48-65 years. Women who exercised had increased bone mineral density in L2-L4 and the femoral neck, as well as improved quadriceps strength, muscular endurance, and peak exercise oxygen consumption (VO2 max), whereas values in the control group declined.[231]

Snow et al found increased BMD of the femoral neck, trochanter, and total hip in 18 postmenopausal women (average age, 64 years) who wore weighted vests and participated in jumping exercises 3 times per week for 32 weeks a year for 5 years.[232]

The results of a Cochrane Database of Systematic Reviews study found that exercise may help prevent bone loss and fractures in postmenopausal women. The most effective type of exercise on BMD for the neck of the femur was found to be non–weight-bearing, high-force exercise, such as lower limb resistance strength training; combination exercise programs were most effective for BMD at the spine.[233]

Although swimming is not a weight-bearing exercise that will improve BMD, it does provide chest expansion, spinal extension, and low-impact cardiopulmonary fitness. Isometric exercises should also be used to strengthen abdominal muscles, aiding in the prevention of kyphosis.

The physical therapist must address balance training, because fall prevention is important in reducing the risk of the clinically apparent manifestation of osteoporosis, fracture. Improving one's balance can significantly lower the risk of falling. Balance training incorporates the strengthening of various parts of the body (eg, trunk, legs), proprioception, and vestibular input. Several different exercises have been shown to be beneficial in patients with osteoporosis.[234, 235, 236, 237]

Tai chi chuan and specific physical therapy programs may be effective in improving balance and reducing falls. Wolf et al monitored 200 elderly community dwellers who received tai chi and computerized balance training. After a 15-week intervention, the authors documented decreased fear of falling responses. In addition, tai chi was shown to reduce the risk of multiple falls by 47.5%.[238]

Campbell et al monitored 233 elderly community dwellers randomized to an individually tailored physical therapy program in the home compared with usual care and an equal number of social visits. The authors found that after one year, the mean rate of falls was lower in the exercise group than in the control group (0.87 vs 1.34, respectively). In addition, after 6 months, persons in the exercise group had improved balance.

Other types of exercise training programs may also positively impact balance and strength. Carter et al demonstrated that osteoporotic women aged 65-75 years who underwent a 10-week community-based physical activity intervention program showed a trend toward improved static balance, dynamic balance, and knee extension strength, although the study failed to show a statistically significant reduction in these fall risk factors, likely due to limited power.[239]

Primary prevention of osteoporosis starts in childhood. Patients require adequate calcium intake, vitamin D intake, and weight-bearing exercise. Beyond this, prevention of osteoporosis has two components: behavior modification and pharmacologic interventions.

The National Osteoporosis Foundation specifies that the following behaviors should be modified to reduce the risk of developing osteoporosis[4] :

• Cigarette smoking
• Physical inactivity
• Intake of alcohol, caffeine, sodium, animal protein, and calcium

Patients should be counseled on smoking cessation and moderation of alcohol intake. Regular weight-bearing exercise and back extensor strengthening help delay bone loss. In a study that found osteopenia in over a quarter of men and women in early middle age, there was a negative correlation between exercise and BMD in the men despite relatively high levels of exercise—but the majority of men in the study reported cycling as their preferred exercise, rather than weight-bearing activities such as walking or running.[76]

Patients who have disorders or take medications that can cause or accelerate bone loss should ensure adequate intakes of calcium and vitamin D  and, in some cases, pharmacologic treatment.[240]  Pharmacologic prevention methods include calcium supplementation and administration of raloxifene or bisphosphonates (alendronate or risedronate). Bisphosphonates should be considered as first-line agents for the prevention of osteoporosis.[241]

In 2017, the American College of Rheumatology published revised recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Recommendations include optimizing calcium and vitamin D supplementation and lifestyle modifications for all adults on long-term glucocorticoid treatment (≥2.5 mg/day prednisone for ≥3 months). Furthermore, categorization of patients by fracture risk (using the FRAX score adjusted for glucocorticoid use) is recommended. First-line pharmacotherapy for patients at moderate-to-high fracture risk is an oral bisphosphonate, which is preferred for safety, cost, and because of lack of evidence of superior antifracture benefits from alternative medications. Other pharmacologic treatments recommended, if oral bisphosphonates are not appropriate, include (in order of preference): IV bisphosphonates, teriparatide, denosumab, and raloxifene.[12]

Estrogen-progestin therapy is no longer considered a first-line approach for the treatment of osteoporosis in postmenopausal women, because it has been linked to an increased risk for breast cancer, stroke, venous thromboembolism, and perhaps coronary disease. Estrogen is now recommended only if patients are also seeking relief of postmenopausal symptoms.

Regular monitoring may be helpful. Periodic bone densitometry helps in diagnosing osteoporosis in the early phase and aids in preventing fractures. According to the National Osteoporosis Foundation, evaluating BMD on a periodic basis is the best way to monitor bone density and future fracture risk.[4] However, there is considerable controversy about how often to repeat BMD measurements, particularly in postmenopausal women with a normal baseline BMD.[242]

Prevention of falls

Environmental measures to prevent falls/fractures include[11] :

• Remove or anchor rugs and use nonskid mats
• Minimize clutter
• Remove loose wires
• Install handrails in bathrooms, halls, and long stairways
• Ensure hallways, stairwells, and entrances are well lighted
• Encourage patient to wear sturdy, low-heeled shoes

For a patient with osteoporosis in the diagnostic and therapeutic phases, the most important consultation is with a rheumatologist or an endocrinologist. These specialists can help obtain the proper laboratory tests and imaging studies needed to rule out causes of secondary osteoporosis. In patients with uncontrolled pain that does not respond to conventional therapies, an invasive pain specialist may be consulted for proper interventional procedures.

A rheumatologist or endocrinologist may also provide useful assistance with management and determination of underlying etiologies in complex cases.

Consultations can include discussions of nonmedical/nonpharmacologic management of osteoporosis.[243, 244] Consult an orthopedist to assist with fracture management. Consultation with a spine surgeon is appropriate for patients with intractable, severe, function-limiting symptomatology from vertebral fractures that has not been relieved by noninterventional techniques. Consultation with a nonsurgical spine specialist is appropriate for a patient who is not a surgical candidate or whose symptoms persist despite surgical fixation.

The US Preventive Services Task Force (USPSTF) 2011 recommendations state that evidence is lacking regarding optimal intervals for repeated screening by dual-energy x-ray absorptiometry (DXA) for individuals with osteoporosis, as well as regarding whether a woman with a normal BMD requires repeated screening. The USPSTF noted that, “a minimum of 2 years may be needed to reliably measure a change in BMD; however, longer intervals may be necessary to improve fracture risk prediction.”[109]

According to a study funded by the National Institutes of Health, osteoporosis will develop in fewer than 10% of older, postmenopausal women during the following rescreening intervals[245] :

• Women with normal BMD or mild osteopenia - Approximately 15 years
• Women with moderate osteopenia - Approximately 5 years
• Women with advanced osteopenia - Approximately 1 year

The following organizations have issued recommendations on measurement of bone mineral density (BMD) for osteoporosis screening:

• American Association of Clinical Endocrinologists (AACE)--(guidelines for postmenopausal women) ^[11]
• National Osteoporosis Foundation (NOF) ^[4]
• International Society for Clinical Densitometry (ISCD) ^[5]
• US Preventive Services Task Force (USPSTF) ^[246]

American Association of Clinical Endocrinologists 

The 2020 update of the American Association of Clinical Endocrinologists (AACE) guidelines recommends evaluation of all women age 50 or older for osteoporosis risk. The initial evaluation should include a detailed history, physical exam, and clinical fracture risk assessment with the Fracture Risk Assessment (FRAX) tool or other fracture risk assessment tool.[11]

BMD measurement should be considered, based on the patient's clinical fracture risk profile. For BMD measurement, axial dual-energy x-ray absorptiometry (DXA)(lumbar spine and hip; 1/3 radius if indicated) is recommended.[11]

The AACE recommends BMD testing in the following patients[11] :

• Women age 65 or older
• Postmenopausal women with a history of fracture(s) without major trauma, with osteopenia identified radiographically, or starting long-term systemic glucocorticoid therapy (≥3 months)
• Perimenopausal or postmenopausal women with risk factors for osteoporosis if willing to consider pharmacologic interventions, with low body weight (< 127 lb or body mass index < 20 kg/m ²), taking long-term systemic glucocorticoid therapy (≥3 months), or with a family history of osteoporotic fracture

Other indications for BMD tesing include the following[11] :

• Early menopause
• Current smoking history
• Excessive consumption of alcohol
• Secondary osteoporosis 

National Osteoporosis Foundation

The 2014 NOF guidelines recommend BMD measurement in the following patients[4] :

• Women age 65 years and older and men age 70 years and older, regardless of clinical risk factors
• Younger postmenopausal women and women in menopausal transition with clinical risk factors for fracture
• Men age 50-69 years with clinical risk factors for fracture

International Society for Clinical Densitometry

The 2015 ISCD Official Positions recommend BMD testing in the following patients[5] :

• Women aged 65 and older
• Postmenopausal women younger than age 65 with a risk factor for low bone mass (eg, low body weight, prior fracture, high-risk medication use, disease or condition associated with bone loss)
• Women during the menopausal transition with clinical risk factors for fracture (eg, low body weight, prior fracture, high-risk medication use)
• Men age 70 years and older
• Men younger than 70 years with a risk factor for low bone mass (eg, low body weight, prior fracture, high-risk medication use, disease or condition associated with bone loss)
• Adults with a fragility fracture
• Adults with a disease or condition associated with low bone mass or bone loss
• Adults taking medications associated with low bone mass or bone loss
• Anyone being considered for pharmacologic therapy
• Anyone being treated, to monitor treatment effect
• Anyone not receiving therapy in whom evidence of bone loss would lead to treatment

Women discontinuing estrogen should be considered for bone density testing according to the indications listed above.

US Preventive Services Task Force

The USPSTF recommends measuring BMD in the following patients[246]

• Women age 65 years and older
• Postmenopausal women younger than 65 years who are at increased risk of osteoporosis, as determined by a formal clinical risk assessment tool

Suggested risk assessment tools include the following:

• Fracture Risk Assessment Tool (FRAX)
• Simple Calculated Osteoporosis Risk Estimation (SCORE)
• Osteoporosis Risk Assessment Instrument (ORAI)
• Osteoporosis Index of Risk (OSIRIS)
• Osteoporosis Self-Assessment Tool (OST)

In contrast to the NOF and ISCD, the USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening to prevent osteoporotic fractures in men.

According to National Osteoporosis Foundation guidelines, a clinical diagnosis of osteoporosis may be made in a postmenopausal woman or in a man over age 50 years who is at an elevated risk for fracture, as indicated by any of the following[247] :

• T-score of -2.5 or less at the spine or hip as determined by dual-energy x-ray absorptiometry (DXA)
• Hip fracture, with or without bone mineral density (BMD) testing
• Vertebral; proximal humerus; pelvis; or, in some cases, distal forearm fracture in the setting of low bone mass (osteopenia) confirmed by DXA
• FRAX score with 10-year risk for hip fracture ≥3% or for major osteoporotic fracture ≥20% in a patient with osteopenia

The 2020 update of the American Association of Clinical Endocrinologists (AACE) guidelines provides the following criteria for the diagnosis of osteoporosis in postmenopausal women[11] :

• T-score −2.5 or below in the lumbar spine, femoral neck, total proximal femur, or 1/3 radius
• Low-trauma spine or hip fracture (regardless of BMD)
• T-score between −1.0 and −2.5 and a fragility fracture of proximal humerus, pelvis, or distal forearm
• T-score between −1.0 and −2.5 and high FRAX® fracture probability based on country-specific thresholds

The National Osteoporosis Foundation (NOF) recommends that pharmacologic therapy should be reserved for postmenopausal women and men aged 50 years or older who present with the following[4] :

• A hip or vertebral fracture (vertebral fractures may be clinical or morphometric [ie, identified on a radiograph alone])

• T-score of –2.5 or less at the femoral neck or spine after appropriate evaluation to exclude secondary causes

• Low bone mass (T-score between –1.0 and –2.5 at the femoral neck or spine) and a 10-year probability of a hip fracture of 3% or greater or a 10-year probability of a major osteoporosis-related fracture of 20% or greater based on the US-adapted WHO algorithm

The 2020 updated guidelines from the American Association of Clinical Endocrinologists (AACE) are similar to NOF guidelines. The AACE strongly recommends pharmacologic treatment of osteoporosis for postmenopausal women with any of the following[11] :

• T-score between −1.0 and −2.5 in the spine, femoral neck, total hip, or 1/3 radius and a history of fragility fracture of the hip or spine 
• T-score of −2.5 or lower in the spine, femoral neck, total hip, or 1/3 radius
• T-score between −1.0 and −2.5 in the spine, femoral neck, total hip, or 1/3 radius, if the FRAX® 10-year probability for major osteoporotic fracture is ≥20% or the 10-year probability of hip fracture is ≥3% (in the U.S.) or above the country-specific threshold in other countries or regions 

A clinical practice guideline from the American College of Physicians (ACP) recommends offering pharmacologic treatment to women with known osteoporosis, to reduce the risk of hip and vertebral fractures.[144] The ACP recommends use of any of the following agents:

• Alendronate
• Risedronate
• Zoledronic acid
• Denosumab

The ACP recommends against the use of estrogen or estrogen plus progestogen or raloxifene for the treatment of osteoporosis in postmenopausal women. Additional recommendations, based on low-quality evidence, include the following:

• In women with osteoporosis, pharmacologic treatment should last for 5 years; generic drugs should be used when possible.

• Monitoring of bone mineral density (BMD) during the 5 years of treatment in women with osteoporosis is not advised, as evidence suggests that fracture risk may be reduced regardless of BMD changes

• For women aged 65 and older who have osteopenia and are at high fracture risk, decisions to treat should take into account patient preference, fracture-risk profile, benefits, harms, and price of medications

• In men with clinically recognized osteoporosis, clinicians should offer bisphosphonate therapy to reduce the risk of vertebral fracture; evidence is lacking on BMD monitoring in men.

Guidelines from the American Association of Clinical Endocrinologists (AACE), updated in 2020, include the following recommendations for choosing drugs to treat osteoporosis in postmenopausal women[11] :

• First-line agents for most high fracture risk patients: alendronate, risedronate, zoledronate, denosumab

• First-line agents for high fracture risk patients unable to use oral therapy: abaloparatide, denosumab, romosozumab, teriparatide, and zoledronate

• First-line agents for spine-specific indications in select patients: ibandronate and raloxifene

• Sequential agents: anabolic agents (eg, abaloparatide, romosozumab, teriparatide) should be followed with a bisphosphonate or denosumab

Combination therapy with two or more agents has not been shown to have a greater effect on fracture reduction than single therapy. The AACE guidelines advise against the use of combination therapy, until the effect of combination therapy on fracture is better understood.[11]

A 2019 guideline from the Endocrine Society on pharmacological management of osteoporosis in postmenopausal women includes the following recommendations[248] :

• Treat patients who are at high risk—particularly those with previous fracture.
• Consider bisphosphonates as the first-line therapeutic choice for postmenopausal women at high risk of fracture.
• Reassess fracture risk after patient has been on bisphosphonates for 3-5 years.
• Following reassessment, prescribe a “bisphosphonate holiday” for women who are on bisphosphonates and are low-to-moderate risk of fracture.
• Consider anabolic therapy (teriparatide or abaloparatide) for women at very high risk of fractures, including those with multiple fractures.
• All women undergoing treatment with osteoporosis therapies other than anabolic therapy should consume calcium and vitamin D in their diet or via supplements.
• Monitor the BMD of high-risk individuals with a low BMD every 1 to 3 years.

The American Society for Bone and Mineral Research (ASBMR), American Association of Clinical Endocrinologists (AACE), Endocrine Society, European Calcified Tissue Society (ECTS) and National Osteoporosis Foundation have created joint Guidance on Osteoporosis Management in the Era of COVID-19 that state the initiation of oral bisphosphonates for osteoporosis should not be delayed in patients at high risk for fracture and provide alternative methods of delivering parenteral osteoporosis treatments and specific recommendations for management of patients who are unable to receive ongoing non-oral osteoporosis medications during the COVID-19 pandemic.

Pharmacologic therapy for osteoporosis includes most commonly the use of antiresorptive agents to decrease bone resorption, such as bisphosphonates, denosumab, and the selective estrogen-receptor modulator (SERM) raloxifene. Pharmacologic options also include anabolic agents to promote bone formation in higher-risk patients with osteoporosis; the parathyroid hormone analogues teriparatide and abaloparatide are anabolic agents. Romosozumab is an uncoupling agent that both stimulates the formation of bone and acts as an antiresorptive. All therapies should be given with adequate calcium and vitamin D intakes.

Class Summary

Calcium metabolism modifiers such as bisphosphonates are stable analogues of inorganic pyrophosphate. Bisphosphonates have a high affinity for hydroxyapatite crystals, and by binding at sites of active bone resorption, these agents can inhibit osteoclastic resorption. All oral bisphosphonates have poor absorption and have a bioavailability of less than 5%. Bone uptake is 20-80%, with the remainder being rapidly excreted through the kidneys.

Bisphosphonates are approved in the United States for the prevention and treatment of postmenopausal osteoporosis, osteoporosis in males, and glucocorticoid-induced osteoporosis. Their major pharmacologic action is the inhibition of bone resorption.

Alendronate (Fosamax); alendronate sodium/cholecalciferol (Fosamax Plus D)

Alendronate inhibits osteoclast activity and bone resorption. By binding to calcium salts, alendronate blocks the transformation of calcium phosphate into hydroxyapatite and inhibits the formation, aggregation, and dissolution of hydroxyapatite crystals in bone. Alendronate increases bone mineral density (BMD) at the spine by 8% and the hip by 3.5%. It reduces the incidence of vertebral fractures by 47% and nonvertebral fractures by 50% over 3 years. Alendronate is approved for the treatment and prevention of postmenopausal osteoporosis, male osteoporosis, and glucocorticoid-induced osteoporosis.

Risedronate (Actonel, Atelvia)

Risedronate is a potent antiresorptive agent that does not affect bone mineralization. The inclusion of an amino group within the heterocyclic ring makes risedronate one of the most potent antiresorptive bisphosphonates. As with other bisphosphonates, risedronate inhibits osteoclast formation and activity. Risedronate increases BMD at the spine by 5.4% and the hip by 1.6%. It reduces vertebral fractures by 41% and nonvertebral fractures by 39% over 3 years. It is approved for the treatment and prevention of postmenopausal osteoporosis, male osteoporosis, and glucocorticoid-induced osteoporosis.

Calcitonin salmon (Miacalcin, Fortical)

Calcitonin is used for the treatment of postmenopausal osteoporosis in women more than 5 years post menopause with low bone mass relative to healthy premenopausal females. Calcitonin-salmon injection should be reserved for patients who refuse or cannot tolerate bisphosphonatse or in whom bisphosphonates are contraindicated. Use of calcitonin-salmon injection is recommended in conjunction with adequate calcium and vitamin D intake to prevent the progressive loss of bone mass. It inhibits osteoclastic bone resorption and has some analgesic effects in patients with fractures.

Although no research data support the idea that the use of intranasal calcitonin reduces the incidence of fractures, studies do show an increase in BMD with the use of calcitonin. Calcitonin increases BMD at the lumbar spine by 1-1.5%. It reduces the incidence of spine fracture by 33% in groups receiving 200 IU/day. It is available in parenteral and intranasal forms; however, the intranasal form is more convenient and better tolerated.

Ibandronate (Boniva)

Ibandronate increases BMD and reduces the incidence of vertebral fractures. Ibandronate increases BMD at the spine by 5.7-6.5% and the hip by 2.4-2.8%. It reduces vertebral fractures by 50% with intermittent (nondaily) dosing over 3 years; it has no effects on reduction of nonvertebral fractures. Ibandronate is approved for the treatment and prevention of postmenopausal osteoporosis. It is available as a 150-mg oral tablet and intravenous solution.

Zoledronic acid (Reclast)

Zoledronic acid inhibits bone resorption by altering osteoclast activity and by inhibiting normal endogenous, as well as tumor induced, mediators of bone degradation. Like other bisphosphonates, zoledronic acid binds to hydroxyapatite crystals in mineralized bone matrix. The binding to calcium phosphates slows the dissolution of hydroxyapatite crystals, as well as inhibits the formation and aggregation of these crystals. It increases BMD at the spine by 4.3-5.1% and at the hip by 3.1-3.5%, as compared with placebo. It reduces the incidence of spine fractures by 70%, hip fractures by 41%, and nonvertebral fractures by 25% over 3 years. Zoledronic acid is approved for the treatment and prevention of postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, osteoporosis in men, and Paget disease of bone. It is contraindicated in patients with severe renal failure.

Class Summary

Parathyroid hormone (PTH) is the primary regulator of calcium and phosphate metabolism in bone and kidneys.

Teriparatide (Forteo, Bonsity)

Teriparatide is recombinant human PTH 1-34, which has identical sequence to the 34 N-terminal amino acids (the biologically active region) of 84-amino acid human PTH. This anabolic agent acts as endogenous PTH, thus regulating calcium and phosphate metabolism in bone and kidneys. It works primarily to stimulate new bone by increasing number and activity of osteoblasts (bone-forming cells).

Additional physiological actions include regulation of bone metabolism, renal tubular reabsorption of calcium and phosphate, and intestinal calcium absorption. Teriparatide increases BMD at the lumbar spine by 9-13% and the hip by 3-6% compared with placebo. When given intermittently, PTH increases bone remodeling with the net effect of increased bone mass and improved skeletal microarchitecture. (This is in contrast to continuous exposure to PTH, which increases bone resorption with a net effect of decreased trabecular bone volume). PTH promotes new bone formation, leading to increased BMD. It reduces the risk of spine fractures by 65% and nonspinal fractures by 54% in patients after an average of 18 mo of therapy. Teriparatide is approved for men or women at high risk of fracture due to primary or hypogonadal osteoporosis or postmenopausal osteoporosis, respectively.

Abaloparatide (Tymlos)

Synthetic peptide analog of human parathyroid hormone-related protein (hPTHrP); hPTHrP is a naturally occurring hormone that, among other functions, regulates bone formation. It elicits anabolic effect on bone, demonstrated by increases in bone mineral density and content that correlated with increases in bone strength at vertebral and/or nonvertebral sites. Daily SC administration for 18 mo was associated with significant reductions in the relative risk for new vertebral fractures (86% reduction) and nonvertebral fractures (43% reduction) compared with placebo. The absolute risk reductions were 3.6% and 2.0%, respectively.

It is indicated for the treatment of postmenopausal women or to increase bone density in men with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy.

Class Summary

Selective estrogen receptor modulators (SERMs) affect some of the receptors stimulated by estrogen but can selectively act as an antagonist or agonist, depending on the organ system. Like estrogen, these are antiresorptive agents. However, because of their selective receptor-modulating property, they provide the beneficial effects of estrogens without the adverse effects.

Raloxifene (Evista)

The biological actions of raloxifene are largely mediated through binding to estrogen receptors, which results in activation of estrogenic pathways in some tissues (agonism) and blockade of estrogenic pathways in others (antagonism). Raloxifene increases BMD at the spine and the hip. It reduces the incidence of spine fractures by 30-55% over 3 years. Raloxifene is approved for the prevention and treatment of postmenopausal osteoporosis in women. It is available as 60 mg tablets that are given orally daily. Adverse reactions commonly seen include hot flashes, leg cramps, peripheral edema, flulike syndrome, arthralgia, and sweating.

Class Summary

Monoclonal antibodies such as denosumab (Prolia) inhibit osteoclast formation, decrease bone resorption, increase BMD, and reduce the risk of fracture. Another monoclonal antibody, romosozumab, binds sclerostin, a regulatory factor in bone metabolism.

Denosumab (Prolia)

Denosumab binds to the receptor activator of nuclear factor-kappa B ligand (RANKL), a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts, which are the cells that are responsible for bone resorption. It is indicated to increase bone mass in men and postmenopausal women with osteoporosis at high risk for fracture. It is also indicated for men at high risk for fracture who are receiving androgen deprivation therapy for nonmetastatic prostate cancer. Additionally, it is indicated for glucocorticoid-induced osteoporosis in men and women at high risk of fracture. The general dosage is 60 mg every 6 months as an SC injection in the upper arm, upper thigh, or abdomen. Patients should be instructed to take 1000 mg of calcium daily and at least 400 IU of vitamin D daily.

Romosozumab (Evenity)

Monoclonal antibody (IgG2) that binds sclerostin, a regulatory factor in bone metabolism. Sclerostin inhibition increases bone formation and, to a lesser extent, decreases bone resorption. It is indicated for osteoporosis treatment in postmenopausal women at high risk for fracture, defined as a history of osteoporotic fracture or multiple risk factors for fracture. It is also indicated for patients who have failed or are intolerant to other available osteoporosis therapy.

Class Summary

Calcium and vitamin D are essential to increase bone density. Vitamin D repletion is essential for calcium absorption. Calcium supplements are used to increase calcium levels.[249] Adequate calcium intake is essential to attain peak bone mass and for continued maintenance of bone health.

Calcium citrate (Cal-Citrate, Cal-Cee, Cal-C-Caps)

Calcium is the primary component of skeletal tissue, providing structural integrity and support for individual growth. Bone undergoes constant remodeling and turnover. A combination of supplemental calcium and vitamin D can potentially lower the incidence of fractures. Calcium citrate is absorbed equally well when taken with or without food.

Calcium carbonate (Caltrate 600, Calcarb 600, Oysco 500, Super Calcium 600, Tums Ultra)

Calcium intake is essential in the prevention and treatment of osteoporosis. Calcium carbonate is generally more inexpensive and requires fewer tablets. Because of its dependence on stomach acid for absorption, calcium carbonate is absorbed most efficiently when taken with food.

Class Summary

Estrogen derivatives are approved for the prevention of osteoporosis and relief of menopause-associated vasomotor symptoms and vulvovaginal atrophy. They are used to increase the serum estrogen level, which, in turn, decreases the rate of bone resorption. The lowest effective dose for the shortest duration necessary should be used. Estrogen therapy reduces bone resorption and retards or halts postmenopausal bone loss. Estrogen therapy is no longer a first-line approach for the treatment of osteoporosis in postmenopausal women because of increased risk of breast cancer, stroke, venous thromboembolism, and coronary disease. The FDA recommends that other approved nonestrogen treatments be considered first for osteoporosis prevention.

Conjugated estrogens (Premarin)

Conjugated estrogens (Premarin)

Estrogens can directly affect bone mass through estrogen receptors in bone, reducing bone turnover and bone loss. Estrogens can also indirectly increase intestinal calcium absorption and renal calcium conservation and, therefore, improve calcium balance.

Estradiol (Estrace, Estraderm, Menostar, Vivelle-Dot, Climara, Estraderm, Alora)

Estradiol restores estrogen levels to concentrations that induce negative feedback at gonadotropic regulatory centers; this, in turn, reduces the release of gonadotropins from the pituitary. Estradiol increases the synthesis of DNA, RNA, and many proteins in target tissues; it also inhibits osteoclastic activity and delays bone loss. In addition, evidence suggests a reduced incidence of fractures.

Estropipate

Estropipate is indicated for the prevention of osteoporosis. The results of a double-blind, placebo-controlled 2-year study have shown that treatment with 1 tablet of estropipate, 0.75 mg daily for 25 days (of a 31-day cycle per month), prevents vertebral bone mass loss in postmenopausal women. When estrogen therapy is discontinued, bone mass declines at a rate comparable to that of the immediate postmenopausal period. There is no evidence that estrogen replacement therapy restores bone mass to premenopausal levels.

Class Summary

Vitamin D is a fat-soluble sterol compound that includes ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). It can be obtained from food and produced by skin when exposed to sunlight of sufficient intensity. When activated in the liver and then the kidney, vitamin D promotes calcium absorption and bone mass. Vitamin D replacement also increases muscle strength and lowers the risk of falling.

Vitamin D (Calciferol, Drisdol)

Vitamin D refers to both ergocalciferol (D2) and cholecalciferol (D3). Following exposure to UV light, 7-dehydrocholesterol (provitamin D3) is converted to cholecalciferol, which is then converted by the liver to calcifediol and then again by the kidney to calcitriol. Vitamin D is available in various forms, including tablets, oral liquid, and capsules. It is commonly coadministered with calcium supplements in patients with osteoporosis.

Class Summary

Estrogen derivatives are approved for the prevention of osteoporosis and relief of menopause-associated vasomotor symptoms and vulvovaginal atrophy. They are used to increase the serum estrogen level, which, in turn, decreases the rate of bone resorption. The lowest effective dose at the shortest duration necessary should be used. Estrogen therapy reduces bone resorption and retards or halts postmenopausal bone loss. Estrogen therapy is no longer a first-line approach for the treatment of osteoporosis in postmenopausal women because of increased risk of breast cancer, stroke, venous thromboembolism, and coronary disease. The FDA recommends that other approved nonestrogen treatments be considered first for osteoporosis prevention.

Norethindrone/ethinylestradiol (Femhrt)

Ethinyl estradiol with norethindrone is used to prevent osteoporosis associated with menopause. When prescribing it solely for the prevention of postmenopausal osteoporosis, therapy should be considered only for women at significant risk of osteoporosis.

Estradiol/norethindrone acetate (Activella, Mimvey, CombiPatch)

Ethinyl estradiol with norethindrone is used to prevent osteoporosis associated with menopause. When prescribing it solely for the prevention of postmenopausal osteoporosis, therapy should be considered only for women at significant risk of osteoporosis.

Class Summary

The combination of conjugated estrogens and medroxyprogesterone reduces bone resorption and retards or halts postmenopausal bone loss.

Conjugated estrogens/medroxyprogesterone acetate (Prempro, Premphase)

The combination of conjugated estrogens and medroxyprogesterone reduces bone resorption and retards or halts postmenopausal bone loss.

Estradiol/levonorgestrel (Climara Pro)

Estradiol/levonorgestrel transdermal system releases both estradiol and levonorgestrel continuously upon application to skin. It is approved for the prevention of postmenopausal osteoporosis.

Estradiol/norgestimate (Prefest)

Estradiol/norgestimate is approved for the prevention of postmenopausal osteoporosis. It is available as a combination of estradiol 1 mg/norgestimate 0.09 mg.